Title: MedChem HS22/FS23

Q: Medicinal chemistry definition
A: Medicinal chemistry is a dicipline that entails the design, synthesis or discovery of new drugs and their development into medicines. It comprises the study of their metabolism, interpretation of their mechanism at the molecular level and the construction of structure-activity relationships.

Q: Classical drug discovery:
A: Isolation and analysis of natural products, structure elucidation, structure modification, total synthesi, testing in vivo models etc.

Q: Modern drug discovery
A: Genomics, proteomics, knock-out/-in mice, ADME, protein biochemistry, structural biology, CRISPR-CAS9 etc.

Strategic questions on pharmaceutical research:

Q: What are the distinct phases of modern target/drug discovery?
A: They can also overlap and run in parallel!

Q: What is preclinical development and what are the goals?
A: The objective is to obtain data that will allow a drug candidate to enter human clinical trials after regulatory approval. Drug candidates undergo extensive in vitro an in vivo studies to predict human drug safety prior to human clinical testing. These studies investigate toxicity over a wide range of doses and the mechanisms by which the drug is metabolised.

Q: What are clinical trials?
A: Tests in humans to determine safety and efficacy, typically three phases.

Q: Phase I clinical trials:
A: Small trials, usually on healthy volunteers to determine safety in terms of dosage and toxicity limits.

Q: Phase II clinical trials:
A: Trials on a larger patient population to evaluate efficacy of treatment and possible side effects.

Q: Phase III clinical trials:
A: Most expensive ones! Large trials of efficacious drugs with tolerable side effects.

Q: What happens after successful clinical trials?
A: Filing of a New Drug Application with regulatory authorities such as the FDA or EMA.

Q: What are the distinct phases of discovery (research)?
A: This is a multisiciplinary process and in the early stages of the reaserch:
- biologists elucidate the disease mechanism, identify potential drug targets and test candidate drugs
- chemists design and synthesise candidate drugs

Q: What are targets?
A: Targets of candidate drugs are biomolecules that ideally play a fundamental role in the onset or progression of a disease.

Q: What are the typical targets of modern drugs?
A: - Enzymes
- Receptors
- Structural proteins
- Carrier proteins
- Nucleic acids

Q: What is very complicated about the effects of a drug in vivo?
A: Biochemical systems encountered by a molecule in vivo are extremely complex: many factors contribute to its final pharmacological effect.

Q: Pharmacodynamics (PD):
A: The study of how a drug interacts with its target.

Q: Pharmacokinetics (PK):
A: How a drug distributes throughout the body in reaching its target.

Q: Properties of a good drug (six):
A: 1. binds to the target molecule with high affinity
2. shows selectivity for the target over other structurally similar biomolecules
3. shows favorable adsorption, distribution, metabolism and excretion in vivo
4. produces the desired therapeutic effect
5. is not toxic
6. can be synthesised economically on large scale

Q: What are the most important features of the peptide bond and what does this mean for proteins?
A: Peptide bonds are planar due to the partial double bond character (resonance conjugation). This is very important for a proteins secondary and tertiary structure. The trans-configuration is usual in proteins to avoid steric clashes.

Q: Primary protein structure:
A: The amino acid sequence:

Secondary protein structure and the most important elements:

Q: Tertiary protein structure:
A: Overall 3D shape and governed by the interactions from the AA side-chains. Also disulfide bonds mediated by cysteine residues play often an important role.

Q: Where do we usually find polar and non-polar residues in a protein structure:
A: Polar residues at the outside (solvation) and non polar residues at the inside (hydrophobic effect). This folding makes it possible for key residues to be placed at their key positions so that the protein can carry out its function.

Q: What determines the function of a protein?
A: Its structure!

Q: Quaternary structure of a protein:
A: Proteins can form complexes with other proteins and assemble thus to a quarternary structure. Interactions between these proteins is usually between the exterior surfaces and therefore ionic interactions are usually the most important. However, protein association can also stabilise water-exposed hydrophobic surfaces (hydrophobic effect).

Explain what is meant by drugability of a target:

Name the five most important functional group interactions in proteins and important also for ligand-protein binding:

Q: What is the thermodynamic nature of protein ligand interactions and what are the pharmacologic consequences of this?
A: It's an equilibrium!

Typical dimensions of k_on of protein ligand interactions:

k_off of protein-ligand interactions:

Q: Dissociation constant of protein-ligand complexes:
A: Usually nanomolar for a typical drug.

Q: Electrostatic interactions:
A: - important ligand-protein interactions
- [$]\Delta G = - 5 \frac{kcal}{mol}[/$]
- loss of binding with distance (1/r) is less than with other bonds: electrostatic interactions are important first interactions between proteins and ligands

Q: How does K_D change with a change of binding energy of 1.6 kcal/mol?
A: An approximate change of a factor of 10.

What can drastically influence the pK_a of charged groups?

Q: Hydrogen bonds:
A: - weak enthalpic bonds between the proton of H-X and another electronegative atom with non-bonded electrons
- H-bonds play a crucial role in stabilising the [$$]\alpha -helices and \beta -sheets[/$$]
- typically [$$]\Delta G = -3 to -5 \frac{kcal}{mol}[/$$], but varies widely

Dipole interactions:

Charge-transfer interactions:

Van der Waals interactions:

What is the role of water in Protein-ligand interactions:

Halogen bonding, cation-pi and pi-pi interactions:

Describe in one sentence the concept of protein-ligand interactions:

Q: Applications of enzyme inhibitors:
A: - in certain diseases
- for treating bacterial infections
- for treating viral infections

Q: Into which two classes can enzyme inhibitors generally be places?
A: Into reversible and irreversible enzyme inhibitors.

Q: How can reversible inhibitors be classified (5 classes):
A: - competitive inhibitors
- stabilisers of an inactive conformation
- alternative substrate inhibitors
- transition state analogs
- slow tight-bindign inhibitors

Q: How do enzymes act as catalysts?
A: - they accelerate the attainment of the equilibrium, they don't change the equilibrium!
- they orient reactive groups using various AA residues to increase the chance of reaction by making transition states easily attainable
- the bind the product weak enough that it can still dissociate
- they participate through acid/base, nucleophilic and electrostatic catalysis

Q: What is an enzyme active site?
A: A reaction surface for the reactants.

What are features of the enzyme active site? (seven points)

Q: What are two typical binding sites for natural product drugs apart from enzymes?
A: - cell membranes (lipid bilayer that is similar to a hydrophobic hydrocarbon solvent)
- structural proteins

Q: What is tubulin and where does it play a role?
A: It is a structural protein, which polymerises to microtobules in the cytoplasm. Polymerisation and depolymerisation of tubulin influences a number of diseases. Microtubules form the cytoskeleton and the mitotic spindle during cell division (important for proliferation of tumors).

How do enzymes lower the activation energy?

What is the concept of induced fit?

Q: Mechanism of [$]\alpha[/$]-chymotrypsin:
A: Hydrolysis of peptides with a catalytic triad of AA-residues:

Q: Acid base catalysis, which residue does this often?
A: Histidine!

Henderson-Hasselbach equation:

Q: Nucleophilic catalysis:
A: Formation of intermediate covalent bond with the substrate. Residues that often are used: Ser, Cys, His, Asp, Glu, Lys.
Ser often acts as a nucleophile in hydrolysis reactions when positioned in close proximity to His, acting as a base.

What are two features of enzymes that are often used for regulation of enzyme activity?

Q: What is feedback control?
A: If an enzyme is inhibited by the product of the reaction.

Q: What are the most important feature of competitive reversible enzyme inhibitors?
A: Competitive reversible inhibitors are displaced from the enzyme active site by higher concentrations of natural substrate.

What are non-competitive irreversible enzyme inhibitors?

What are non-competitive reversible enzyme inhibitors?

Q: What are transition state analogues?
A: Transition state analogues or transition state isosteres are drugs that structurally resemble the transition state of the catalysed reaction.

Q: What are suicide substrates?
A: Suicide inhibitors are converted by enzymes to species which inactivate enzymes.

Q: What are isoenzymes and how do they influence enzyme inhibitor selectivity?
A: Isozymes are from different genes but catalyse the same reaction. They differ in AA sequence. Drugs which are isoenzyme selective are less likely to be toxic and can be used to treat different diseases.

Q: What is the Michaelis-Menten equation?
A: It is used to describe enzyme kinetics.

Q: Why are enzyme kinetics important for drug development?
A: Enzyme kinetics are studied in order to understand and improve enzyme inhibitors. Measurement of enzyme kinetics allows comparison of enzyme inhibitor potencies (potency is the concentration of the drug required for a defined effectiveness).

How can Michaelis-Menten kinetics be used to determine wheter an inhibitor is acting competitively or non-competitively?

Which quantities are used to compare the activity of enzyme inhibitors when selecting drug candidates?

Q: What is the most important role of receptors?
A: They are crucial for cell-cell communication. They transmit a message into the cell leading to a cellular effect. Different receptors on the same cell are slective for different chemical messengers.

Q: Where are most receptors located?
A: Most receptors are located in cell membranes and receive chemical messangers from other cells.

What are two distinct types of chemical messangers?

What are the four main types of receptor family drug targets?

Draw a simple scheme of the communication in the CNS:

Q: What are the most important chemical messengers?
A: Biogenic amines!
And also amino acids, purines, neuropeptides and peptide hormones.

Dopamine:

Histamin:

L-Dopa, its synthesis and the synthesis of Dopamin:

Synthesis of Histamine:

Q: L-Noradrenalin and it's synthesis:
A: Oxidation from Dopamin:

Q: L-Adrenalin and its synthesis:
A: Oxidation from Histamin:

Q: GABA, stucture and synthesis:
A: [$$]\gamma[/$$]-Aminobutyric acid

Serotonin und synthese:

Acetylcholin and biosynthesis route:

Q: Receptor types and subtypes:
A: Types and subtypes reflect differences in receptors for the same ligand. Receptors types and subtypes are distributed unequally across tissues.

Principle of ligand binding to receptors:

Q: Why are receptors important in medicine:
A: - cell-cell communication is important for the human body: dysregulation of messengers/receptors leads to over-activity or down-regulation of cell sognaling
- dysregulation can be corrected with drugs: 1) agonist drugs can function as replacements for natural messengers 2) Antagonist drugs compete with the natural messenger and act as inhibitors of over-active signaling
- drugs that interact with receptors are important in medicine for example for pain treatment, depression, Parkinson's disease and many more
- different receptor subtypes are pharmacologically important for different drugs

Ion channels as receptors and the most important features:

Q: What are receptors involved in the control of cationic ion channels?
A: Nicotinic receptors, glutamate receptors, 5HT_3 receptors and ATP receptors.

Q: What are anionic channels for chloride ions?
A: GABA_A and glycine receptors.

Q: How many families of ion channel coupled receptors are there and how are they classified?
A: They are classified by the number of transmembrane domains (4-TM, 3-TM, 2-TM).

Q: How is selectivity of the different ion channels achieved?
A: It is dependent on the AA residues lining the channel.

4-TM channels:

3-TM ion channels:

2-TM ion channels:

Q: GPCRs most important features:
A: G-Protein coupled receptors.
- GPCRs are single proteins with 7 TM regions
- have external messenger binding sites on the cell which activate internal enzymes: different receptors can activate the same enzyme

Q: Ligand binding to GPCRs:
A: - GPCRs fall into several categories based on sequence similarities and ligands
- the ligand binding site varies depending on the ligand type
- ligand binding sites are target binding sites for drugs
- compound screening usually involves cellular assays

Agonist drugs acting on GPCRs:

Partial agonists:

Inverse agonists:

Antagonist drugs against GPCRs:

Competitive antagonists:

Non competitive (irreversible) antagonists:

Non competitive (reversible) allosteric antagonists:

Where are the allosteric binding sites for allosteric drugs in GPCRs:

Q: What are the three main signal transduction pathways through GPCRs:
A: - Via adenylylcyclase
- via Phospholipase C, activating PKC and PKB
- via Phospholipase C only activating PKC

General GPCR signaling mechanism:

GPCR signal transduction via cAMP:

ATP:

cyclic-AMP:

Q: GPCSs: Signal transduction as a drug target:
A: - a signal transduction pathway provides several points of intervention for drugs
- drugs can be designed to several targets in a disease-related pathway
- redundancy in a pathway may render a drug ineffective
- the more at the "top" of a signaling pathway, the more side-effects are probable also in other tissues as the signaling parts at the "beginning" are often involved in several different receptor signaling pathways

GPCRs: Signal transduction via phospholipase C:

IP3:

PIP_2:

Q: DAG:
A: Diacetylglycerol

What is important for agonist and antagonist designs?

Q: What is a difficulty with targeting nucleic acids with drugs?
A: RNA and DNA can be considered as receptors, but their heavily solvated structures present difficulties for the development of potent and selective drugs.

Q: Where does toxicity of DNA targeting drugs against aberrant cell growth occur?
A: In tissues where rapid cell division occurs: mucosa, hair, bone marrow

Adenosine:

Guanosine:

Cytidine:

Thymidine:

Q: How are nucleosides linked?
A: By a predominantly negatively-charged phosphodiester backbone:

Explain quickly the most important features about DNA structure:

How is DNA packaged into the cell?

Q: What different types of RNAs exist?
A: - transfer RNA (tRNA)
- ribosomal RNA (rRNA)
- messenger RNA (mRNA)
- micro RNAs (miRNA)
- long non-coding RNAs
- etc.

Q: How does RNA differ from DNA?
A: Uracil replaces thymine in RNA and the sugar is ribose instead of deoxyribose.
RNA is most often single stranded with regions of stong secondary structure.

What is the structure of a tRNA?

What are the types of drugs acting on DNA? (four) What are their mechanisms?

What are drugs acting on RNA and what are their mechanisms of action? (two)

Drugs acting on topoisomerase II and their mechanism:

Q: Derivatives of epipodophyllotoxins:
A: Drugs targeting topoisomerase II

DNA alkylating agents mechanism of action, side effects and origin:

Q: Which are the nucleophilic groups on the DNA bases?
A: Generally, nucleophilicity is weak and the reactivity depends on the electrophile.

Chloromethine - structure and mechanism of reaction:

What would be the properties of ideal DNA alkylating agents?

What are examples of DNA alkylating agents derived from mustards?

Q: Mephalan:
A: Mimics phenylalanine: given orally for multiple myeloma, ovarian and breast cancers; L- and D- isomers have equal potencies.

Q: How can a DNA alkylating agent be made less reactive?
A: The aziridium is made less reactive by conjugation to electron withdrawing groups as f.ex. a carbamate in Estramustine.

Q: Methyldiazonium:
A: It is a DNA alkylating agent and produced from dacarbazine in the liver.

Q: Cisplatin:
A: It is a DNA alkylating agent.

Q: How are side-effects of drugs often handeled?
A: Just give them another drug, which treats the side effects... :(

Q: What are drugs derived from cisplatin and why were they developed?
A: Often drugs can be modfied to improve certain properties.

DNA intercalating agents, general structure and mechanism:

Q: What are anthracyclines?
A: DNA intercalating agents.

Q: What is always the goal when optimising a drug?
A: Make it more specific and less toxic.

DNA cleaving drugs (one example):

The "antisense" concept for drugs acting on mRNA:

Name four hurdles in the development of oligonucleotide drugs:

The RNase H mechanism:

RNAi mechanism:

Q: Explain which length of oligonucleotide is theoretically long enough for targeting RNA but what the drawbacks are:
A: The minimul theoretical length is 16 nt.

Q: What can be done to tune oligonucleotide stability?
A: By subtle modifications of the backbone of the oligonucleotides as f.ex:

What are the characteristics of a target in medicinal chemistry?

How was target selection carried out historically?

What is the modern process of drug discovery?

Q: Which are the three approaches commonly used in target selection?
A: 1. Whole animal models
2. molecular targeting f.ex. high-throughput sequencing showed protease cathepsin K is highly expressed in bone resorption cells (osteoporosis)
3. population genetics

Disease models: Why are they used? What are properties of an ideal disease model?

Q: What are factors that need to be considered when cchoosing a disease model?
A: - they vary widely as predictors of disease
- generally, the relevance and experimental complexity of the model for the disease can be very different and increases from:
- Choose a model only as complex as necessary, providing you with as much insight as possible

Q: What does it mean when a target is not valid?
A: When compounds show no clinical efficacy and thus the underlying biological hypothesis about the target's role in the disease may be incorrect.

Unvalidated vs. validated targets:

Quickly describe what is meant by the process of target validation:

Q: What validates the target?
A: Only results in the clinic validate a target i.e. the compound validates the target!

With the example of the Bcr-Abl gene fusion, explain what the properties of an ideal drug target are:

What is considered to be an optimal drug target according ro the pharmaceutical industry? (six aspects)

Q: What is a lead compound?
A: - A lead compound is the starting point for a medicinal chemistry project.
- It is not the final drug!
- It has a detectable level of pharmacological activity in an assay.
- It has a chemical structure which permits optimisation of its pharmacokinetic and pharmacodynamic properties by medicinal chemists.

What is required for the identification of a lead compound as a starting point for medicinal chemistry?

Q: Which two "class" of compounds are analysed for the identification of a lead compound?
A: 1. Random compounds from very large libraries and they are tested without regard of their structure
2. Rationally designed compounds from analysis of natural ligands, from the 3D structure of the target, from competitor compounds etc.

In vitro assays are carried out on:

What are in vitro tests suitable for and what are the drawbacks?

Q: Name two types of in vitro assays:
A: - enzyme inhibition assays
- receptor assays

What is an enzyme inhibition assay?

What is a receptor assay?

Describe what in vivo assays are and how they are usually carried out:

What are in vivo assays carried out for?

Describe in one sentence what high-throughput screening is:

Quickly outline the work-flow of a high throughput screening:

Q: What could be a typical observable to characterise the activity of a coumpound in a HTS?
A: Flourescence. F.ex. an enzyme that converts a substrate (which generates fluorescence i.e. freeing a fluorophore upon conversion) can be screened for an inhibitor, which will thus decrease the fluorescence signal and can be easily read out.

Q: What does HTS provide?
A: It provides hits for optimisation.

Q: What are drawbacks of HTS?
A: It is "quick and dirty". Some compounds often score in HTS because of non-specific effects.

What are the two sources from which compounds are selected for HTS in assays during the identification of chemical leads?

Q: Why are natural products often chosen as leads?
A: - many of today's medicines are derived from natural products
- natural products evolve to target essential proteins in organisms which they co-evolve --> they were already optimised by nature

Q: What are the drawbacks of natural products as leads?
A: - they are often highly complex structures which are not economically viable drugs if synthesised chemically --> if they are manufactured as drugs biochemical synthesis is often used
- they are often available in small quantities from their natural sources to allow characterisation and testing

Chloroamphenicol --> an antibacterial

Q: Why are toxins and venoms often good leads?
A: They are extremely toxic because of very high affinity interactions with certain receptors. Also here we thus have already some optimisation by nature.

Q: Why is structural biology an important tool for rational approaches to leads?
A: --> there is already a lot around, so use it!

Q: How is serendipity important in rational approaches to leads?
A: Side-effects seen in clinical trials have led to the use of drugs for different indicatio!

Q: What are so-called "Me-too" compounds?
A: Researchers in pharma often use competitor patens as starting points from chemistry. Another company has developed a drug for a certain disease? Let's take it as a lead structure and make it better!

Q: What are the properties of a lead compound?
A: - has some level of pharmacological activity
- a structure, which permits optimisation of PD and PK such as target affinity, target selectivity, water solubilits, chemical stability etc.

What is the Pharmacophore?

Q: What is the auxophore and how can it be used?
A: Groups not involved in the binding interactions are the Auxophore. They may even hinder efficient binding and thus these groups can be modifed to modify the PK properties.

What are the structure activity relationships?

Q: What is the IUPAC definition of a pharmacophore?
A: --> don't know by heart just general gist

Q: How is the SAR constructed?
A: Leads are optimised by chemically modifying functional groups and structural parts in the molecule and measuring effects on the PD and PK. These changes allow the construction of a Structure-Activity relationship.

Q: What can be important aspects in lead optimisation?
A: - the ease of synthesis may be more important than cogent rationale
- only do one step/modification at a time
- opportunism, intuition and luck play important roles in optimisation

What time is usually devoted to lead optimisation?

How are conclusions on PD and PK drawn on the lead structure?

Q: How are alcohols usually converted in leads to assess their importance?
A: Since alcohols are often HBDs and HBAs, they are often modified to ethers and esters to change their properties.

How are amines usually converted in lead optimisation to assess their importance in PD and PK?

How are amides usually converted in lead optimisation to assess their importance on PD and PK?

How are carbonyls usually modified during lead optimisation to assess their importance on PD and PK?

How are acids usually converted during lead optimisation to asses their importance on PD and PK?

How are alkenes usually converted during lead optimisation to asses their importance on PD and PK?

How are alkyl groups usually converted during lead optimisation to asses their importante on PD and PK?

What are the characteristics of the Morphium family members?

Morphine

They belong to the Morphine family!

Pharmacophore of morphine:

What are the usual effects of modifying the pharmacophore?

For what can the total synthesis of complex natural products be useful for?

In which cases is the simplification of complex leads desired and why?

Q: What is a prerequisite for structure-based drug design and how is it achieved?
A: - you need the structure :)
- if the protein can be isolated and crystallised it becomes possible to determine its structure using x-ray crystallography

How is structure-based drug design achieved?

Q: What are the caveats of structure based drug design and how does this influence the drugability of a target?
A: You prefer to work on a target of which you know the structure than one where you don't!

How can rigidifying a structure during lead optimisation be beneficial?

What is bioisosterism and how is it used during optimisation of a lead?

What is the classical description of isosteres?

What are non-classical bioisosteres?

Bioisosteres of the carbonyl group:

What are bioisosteres of the carboxylic acid group?

What are Bioisosteres of the ester group?

What are Bioisosteres of the hydroxyl group?

What are bioisosteres of the catechol group?

Classical bioisosteres of -CH_3 and -Cl?

Q: What is important for a drug to get again out of the blood stream?
A: So if it's too hydrophobic, it can bind strongly to plasma proteins and will this not exit the blood stream easily.

Whar are the effects/considerations of the cell membrane for PK?

Q: What are considerations for the aqueous solubility of a drug?
A: - blood is an aqueous environment so for the drug to be delivered efficiently it should have some aqueous solubility
- drugs with poor water-solubility can precipitate in vessels and organs
- in general, the higher the ratio of polar groups to the total number of carbon atoms, the more water-soluble the compound --> you can add polar groups to your lead to make it more water-soluble
- water solubility can be improved by salt-formation, ionisation or formulation

Q: How can water solubility be improved? (three points)
A: - disrupt crystal packing since it can affect water solubility quite drastically
- make a salt of your compound
- make it ionic

Q: Advantages and disadvantages of ionisation:
A: Advantages:
- can make your compound more water soluble
- important interactions for drug-target binding
Disadvantage:
- it hinders cell membrane penetration

Q: Why is it good if a compound is only partially ionised at pH 7?
A: - it improves water solubility but still allows for better cell penetration since a certain amount of the drug is not charged and can better cross the cell-membrane

How is the lipophilicity of a compound determined?

What is the partition coefficient P and what does it tell us about the Lipophilicity of a drug?

What is alkyl chain homologtion and how can it affect PK?

How can you distinguish whether the effect of alkyl chain homologation arises from PK or PD?

Q: For which localisation of your target is lipophilicity incredibly important?
A: If it should go into the brain!!!

What characterises the blood brain barrier (BBB)?

What is drug absorption?

How do you select the way of administration of a drug?

What is oral bioavailability?

What is the "path" of orally-given drugs and where do challenges arise?

What is the so-called first-pass effect of orally-delivered drugs?

What is Lipinski's rule of five?

What are the five rules of Lipinski?

Rules for carboxylate containing oral drug candidates to predict oral absorption:

Q: Intraveneous injection as a drug administration:
A: This is not the most desired way, as the administration can often not be done by the patient himself.

When are intramuscular injections used?

What is sub-cutaneous injection often used for?

Pulmonary delivery of drugs, what is it often used for?

Q: Can drugs also just be applied to the skin?
A: Yes, but very rarely.

What are intrathecal injections?

What is the sublingual route of administration?

What are advantages of giving drugs via the rectal route?

Why does the body metabolise drugs?

Where does drug metabolism usually take place?

Q: Are all drugs metabolised?
A: No, some are also just excreted unmetabolised.

Why does drug metabolism complicate medicinal chemistry? (four points)

How can drug metabolism be divided?

Q: How can we exploit drug metabolism?
A: In some cases the active form of the drug is a metabolite of the administered compound. --> concept of prodrug Design something that is well orally available and is then converted into the actual drug by the metabolism.

How are drug metabolites usually characterised?

How is phase I metabolism effected?

Which structures are most prone to oxidation by phase I metabolism?

Which structures are most prone to reduction by phase I metabolism?

Which structures are most prone to hydrolysis by phase I metabolism?

What are P450 enzymes?

What are typical P450 catalysed oxidative reactions on carbon?

P450 catalysed oxidation reactions on alcohols and aldehydes:

Oxidation of alkenes and aromatic rings by P450 enzymes:

How are "exposed" alkyl groups and exposed regions of cycloalkyl rings usually oxidised?

How are activated carbon centers next to sp^2 and sp carbons oxidised by P450 enzymes?

How are the activated carbons of amines, esters and thioesters oxidised by P450 enzymes?

How are alkyl halides usually oxidised by P450 enzymes?

How are nitrogen-containing functional groups usually oxidised by P450 enzymes?

How are sulfur containing functional groups usually oxidised by P450 enzymes?

How are phosphorous containing functional groups usually oxidised by P450 enzymes?

Q: What are Flavin-containing mono-oxygenases?
A: They are enzymes which oxygenate drugs at N, S and P.

Oxygenation products from Flavin-containing mono-oxygenases:

How can aromatic hydroxylation at the para-position be avoided?

How can oxidation of methyl groups to carboxylic acids on aromatic rings be prevented?

How can P450 enzymes reduce at carbon centers?

How can P450 enzymes reduce at heteroatom centers?

What are most phase II metabolism reactions?

Q: Name six common phase II metabolism reactions:
A: 1. Glucuronic acid conjugation
2. Sulfo transfer
3. Amino acid transfer
4. Glutathione conjugation
5. Methylation
6. Acetylation

Q: What is glucuronic acid conjugation and it happens for which functional groups?
A: A common Phase II metabolism step.

Which functional groups ar sulphated in phase II metabolism? Which functional groups form stable sulphates and which not?

Which functional group forms amino-acid conjugates?

Which functional groups are metabolised via glutathione conjugation in phase II metabolism? How and where is this reaction catalysed?

Which phase II metabolism reactions decrease polarity?

Which functional groups are methylated by phase II metabolism?

Q: Which one is the most important methyltransferase in the body?
A: The catechol methyltransferase!

Which functional groups are acetylated by phase II metabolism?

What are advantages when it comes to target selection for infectuous diseases?

Q: What is the biggest challenge with antibacterial drugs?
A: The usually rapid development of resistances!

Q: How do bacterial cells differ from human cells (four points) and why is this beneficial?
A: It provides some unique targets!

What are the five main mechanisms by which antibacterial agents act?

What is the definition of an antibiotic?

What is the general structure of penicillins?

How are penicillins usually biosynthesised?

Q: What are the properdies of benzylpenicillin?
A: - bactericidal against rapidly dividing bacteria only
- bactericidal against non-beta-lactamase producing gram-positive bacilli
- inactive against many gram negative bacteria
- inactive when taken orally: degraded in the stomach
- non-toxic: one of the safest drugs known but can cause allergic reactions

Q: What is the mechanism of action of penicillins?
A: Penicillings inhibit the transpeptidase in a crucial step for the cell wall biosynthesis.

How does penicillin act directly on the transpeptidase?

Which molecule does penicillin mimic?

How does drug resistance emerge?

Which drugs are least susceptible towards resistance by bacteria?

How is resistance transmitted among bacteria?

Where does resistance to penicillins derive from? (five points)

Q: What are beta-lactamases?
A: This renders penicillins inactive.

Q: What is meant by antibiosis in context with penicillins?
A: We use penicillins to kill bacteria. Bacteria have developed beta-lactamases to inhibit penicilin. We have developed beta-lactamase inhibitors to render penicillin active again.

Q: What is the SAR of penicillins?
A: Variations on penicillins are restricted to the acylamino side chain.

What are three challenges medicinal chemistry faced with penicillins?

How are antibiotics commercially produced? (seven steps)

Q: What is 6-APA and what is it used for?
A: Easily make a wide range of penicillins!

Q: Why are penicillins prone to acid hydrolysis?
A: Due to the high ring-strain and a highly reactive (electrophilic) beta-lactam carbonyl.

Q: Why is the beta-lactam carbonyl so electrophilic?
A: No conjugation!

What modification reduces beta-lactamase activity?

Which factors determine whether a particular bacterial strain will be susceptible to a penicillin (four)?

What are so-called broad-spectrum antibiotics?

Q: What are aminopenicillins?
A: A class of broad-specturm antibiotics with alpha-hydrophilic groups:

Q: Name three calsses of broad spectrum penicillins:
A: 1. Aminopenicillins
2. Carbxypenicillins
3. Ureidopenicillins
All of them have in common that they contain alpha-hydrophilic groups. The stereochemistry at the alpha carbon is important: only one diastereomer is active.

Q: What are carboxypenicillins?
A: A class of broad spectrum antibiotics:
They have a carboxyl group alpha to the acyl side chain.

Q: What are ureidopenicillins?
A: They are a class of broad-spectrum antibiotics with a urea functionality at the alpha position.

Q: What is clavulanic acid and what is it commonly used for?
A: Co-administration of clavulanic acid with penicillins permits reduced doses of penicillins.

Q: How does Clavulanic acid inhibit beta-lactamases?
A: It is an irreversible inhibitor!

Q: What are typical beta-lactamase inhibitors?
A: - clavulanic acid
- sulphones

Q: What does 6-APA stand for?
A: 6-aminopenicillanic acid --> precursor for the synthesis of many penicillins

Q: How can we make penicillins more resistant towards acid hydrolysis?
A: Add electron withdrawing side-chains!

What is a prodrug?

What problems can be adressed through the design of a prodrug?

What need to be considered on a case by case basis for pro-drugs?

In which case is the prodrug strategy usually tried?

How can pro-drugs be grouped?

What is a typical pro-drug strategy for penicillins?

Esters as prodrugs: How to determine which ester?

Q: Why are esters good pro-drugs? What can be a problem with these esters?
A: The groups cleaved from the ester should not be toxic!

Which is a commonly employed prodrug strategy to increase solubility?

Why does sometimes the solubility of a drug need to be decreased with a pro-drug strategy?

For which application are phosphate pro-drugs usually employed?

How are phosphate pro-drugs usually converted into their active structure?

For what can N-methylation be used in a pro-drug strategy?

Q: How can drugs be modified to be stored in the fat tissue?
A: Also a pro-drug strategy.

Q: What is meant by co-drugs?
A: It is not a given that two drugs, which need to act together will be transported in the same way and in the required amounts to the same cells. --> fuse them together in a molecule that can be cleaved
F.ex. for beta-lactamase inhibitor and a penicillin

Q: What are cephalosporins and their properties?
A: - a major group of beta-lactam antibiotics
- relatively weak antibacterial activity
- better stability against acid hydrolases and to beta-lactamases

How are cephalosporins biosynthesised?

Q: What is the mechanism of action of cephalosporins?
A: Esterases cleave the ester and reduce the activity of the drug.

Q: What is 7-ACA?
A: A precursos to make different cephalosporins.

Against which types of bacteria do cephalosporins work best?

Q: What is important about the newest generation of cephalosporins?
A: They have been developed as broad-spectrum agents and even show activity against some multi-resistant strains.

Q: What is D-cycloserine?
A: It is an inhibitor of bacterial cell wall synthesis and mimics the structure of D-Ala-D-Ala. It has broad spectrum activity.

Q: What is Vancomycin?
A: - it is a narrow-spectrum bactericidal glycopeptide
- it is often the last resort in treating drug resistant infections and is used sparingly
- it cannot cross Gram-negative cell membranes and is inactive

Q: What is the mechanism of action of Vancomycin?
A: It binds to the cell wall gycopentapeptide:

Q: What are tetracyclines?
A: - bacteriostatic antibiotics with broad spectrum activity
- inhibit protein synthesis by binding to ribosomal 30S subunit and preventing aminoacyl-tRNA binding --> prevents the further addition of amino acids to the growing chain

Q: What is Ciprofloxacin?
A: It's a nucleic acid inhibitor of transcription/replication. Target is the bacterial gyrase and topoisomerase.

Q: What are sulphonamides?
A: A class of antibiotics that inhibit metabolism.

A sulphonamide antibiotic, however no longer sold.

What are antimetabolites?

Q: What is the mechanism of action of sulphonamides?
A: They are bacteriostatic: they inhibit the majority of bacterial cell growth and allow host mechanisms the time to eradicate infections.
It inhibits the production of tetrahydrofolate, which is necessary fo the survival of bacterial cells.

Why do sulphonamides only inhibit the growth of bacterial cells and not human cells?

Q: What is the principle behind a bacteriostatic drug?
A: They inhibit the majority of bacterial cell growth and allow host mechanisms the time to eradicate the infection.

Q: Which are the most common types of pro-drugs?
A: Esters

What are drug-drug interactions?

What is a common example of drug-drug interactions?

Q: How can diet affect a drug?
A: F.ex. grapefruit juice
If f.ex. metabolism of a drug or pro-drug is slowed down it can accumulate to toxic levels.

Pepetic ulcers:

Q: What is the mechanism for the release of gastric acid?
A: - gastrin stimulates the release of gastric acid

Q: What was the first treatment option for ulcers?
A: - antiacid bicarbonates and carbonates but thee effects were only short-lasting and there were side effects

Q: How did understanding the mechanisms of gastric acid secretion help improve the development of drugs against peptid ulcers?
A: It allowed the identification of multiple routes of intervention. The use of antiacid bicarbonates and carbonates was no longer necessary.

Which property of histamine is very important for the binding to histamine receptors?

Q: What is the structure of classical anti-histamines?
A: - two aryl rings and an alkyl chain

Q: What was the clue that the histamine receptor involved in gastric acid secretion has to be a new one, which is not known yet?
A: Classical anti-histamines had no effect on gastric acid secretion. Further, 5-methylhistamine was found to stimulate gastric acid but had weak activity for all other actions of histamine in assays.

Quickly explain how Burimamide validated the H_2 receptor as a target for peptic ulcers:

How to try to produce an antagonist to a receptor starting from the structure of the natural ligand?

Q: What is usually the "guilty party" for toxicity of a drug?
A: If the structure contains a sufur. It's most likely the sulfur.

Q: What is cimetidine?
A: A drug derived from Histamine that acts as an antagonist on the H_2 receptor.

Q: How do substituents on guanidines change the pKa? Why can this be important?
A: It can be important to tune the pKa of a drug and thus improve its PD and PK properties. This was f.ex. super important for the development of the H_2 receptor antagonists for peptic ulcer treatment.

Which class of compounds have superseded the use of H_2 receptor antagonists for the treatment of peptic ulcers?

How does the proton pump in the stomach work?

Q: What is the common mechanism of action of proton pump inhibitors (PPIs)?
A: They are deprotonated at a pH of 7 but get protonated and thus activated at the low pH inside the stomach.

Why do PPIs have only few side-effects? (five points)

Q: What is the concept of chiral switching?
A: F.ex. using a chiral catalyst in the final oxidation step to synthesise the desired enantiomer of Omeprazole (PPI inhibitor)

What role does Helicobacter Pylori play in the development of peptic ulcers and how does it survive in the stomach?

Q: How did the discovery of the role of helicobacter pylori influence the course of treatment of peptic ulcers?
A: If a patient is tested positive for H. Pylori and has a peptic ulcer, they are usually treated with 1 PPI and 2 antibacterials which is a highly effective treatment.

Q: What are peptic ulcers?
A: Localised areas of inflammation in the mucous membranes of stomach and duodenum.

What are the two components of the nervous system?

Which two types of nerves does the PNS have?

Q: Which are the two main neurotransmitters in the PNS?
A: 1. acetylcholine
2. noradrenaline

Acetylcholine vs. noradrenaline in the PNS:

Where is noradrenaline released in the PNS?

What is adrenaline?

How do neurotransmitters at synapses work?

Q: How is neurotransmission also controlled?
A: Transmission is also regulated by co-transmitters.

What are co-transmitters of noradrenaline?

What is the two-state model for drug-receptor interactions?

Q: What are the receptros for adrenaline and noradrenaline?
A: The beta- and alpha-adrenergic receptors.

How is the biosynthesis of dopamine, noradrenaline and adrenaline regulated?

What is the relationship between dopamine and Parkinson's disease?

Q: What is a problem for the treatment of Parkinson's disease?
A: Dopamine itself does not cross the BBB. Metabolism on Levodopa complicates the use of it as a treatment of Parkinson's. Thus, a lot of inhibitors together with Levodopa are in theory needed to effectively increase the dopamine concentration in the brain.

What is Levodopa?

Levodopa

How can the stability of levodopa in the periphery be increased such that higher amounts cross the BBB and side-effects are reduced?

Q: Which types of compounds need to be coadministered with levodopa to ensure large amounts can cross the BBB?
A: The co-administered compounds should not cross the BBB!
1. inhibitors of decarboxylase
2. inhibitors of catechol methyltransferase
3. inhibitors of monoamide oxidases

Q: What type of receptors are adrenergic receptors?
A: GPCRs

What are the physiological responses upon release of adrenaline?

What are the effects of adrenergic receptor agonists?

What are the effects of adrenergic receptor antagonists?

Q: Why does adrenaline cause a lot of side-effects?
A: Because it has no selecticity for the alpha- or beta-adrenergic receptors.

Q: Which types of compounds are usually used for the treatment of asthma?
A: beta_2-adrenergic receptor agonists

Used for the treatment of asthma. Leads were optimised in selectivity for the beta_2 subtype to reduce side effects. This is a nice example of how the existence an knowledge on the different types and subtypes of a receptor can be important.

Q: SAR of beta_2 adrenergic receptor agonists:
A: Always keep an eye on the scaffold of the original ligand --> adrenaline here.
In this case the extra hydrophobic binding pocket of the beta adrenergic receptor is very important for improving the selectivity over the alpha type.

Q: What are beta-adrenergic receptors used for to treat?
A: They are used to treat hypertension.

Q: Propanolol:
A: Beta blockers are used to treat hypertension.

Q: What are the anti-hypertensive activities resulting from beta blockers and what can be tricky?
A: Again we want a compound that is selective for the adrenergic beta subtype, which is responsible for the desired symptoms and not target also other subtypes, which lead to the side effects. In case of hypertension, we want to antagonise the beta_1 receptor.

Q: Which are the most used adrenergic antagonists in medicine?
A: The beta blockers.

Q: What are the two important sub-systems of the motor nerves?
A: - somatic system
- autonomic system

How is acetylcholine synthesised and degraded again in vivo?

The mechanism of action of acetylcholine as a neurotransmitter at synapses:

Q: Which are the two types of receptors of acetylcholine that lead to different pharmacological effects?
A: The nicotinic and muscarinic receptors

Nicotine --> an acetylcholine agonist

Muscarine --> an acetylcholine agonist

Where are nicotinic receptors active?

Where are muscarinic receptors active?

Why is acetylcholine itself not useful as a drug?

How can drugs derived from acetylcholine be made more stable? However, what needs to be considered still?

How can the selectivity for muscarinic receptors over nicotinic receptors be achieved?

vs.

Q: What types of receptors are muscarinic receptors?
A: They are GPCRs.

Many of today's anticholinergics are derived from this structure.

Map the structure of acetylcholine onto atropine:

What are clinical uses of muscarinic antagonists?

Q: How can the side-effects of atropine such as hallucinations be reduced?
A: Make a quarternary salt that cannot cross the BBB.

What is the concept of biotopic ligands for subtype selectivity?

What type of receptor is the nicotinic receptor?

What is the use of nicotinic antagonists?

Q: What is a very common feature in nicotinic antagonists?
A: They contain two acetylcholine-like fragments in one molecule.

What is the function and importance of acetylcholinesterase?

Q: What is the mechanism of acetylcholinesterase?
A: It is a "usual" esterase and contains a catalytic triad Ser:His:Asp in the active site.

What is the mechanism of action of acetylcholinesterase drugs?

What are irreversible inhibitors of acetylcholinesterase and how do they work?

What is the mechanism of action of pralidoxime, an antidote for organophosphorous poisoning?

Q: What are the general characteristics of opioids?
A: - they are among the oldest drugs and one of several classes of pain killers

Q: Morphine effects:
A: - acts in the brain
- effective against nociceptive pain (injury to muscle/tissue)
- elevates the pain threshold in the brain --> doesn't "remove" the pain

Q: What are the side effects of morphine?
A: - respiratory depression
- constipation
- excitation
- euphoria
- nausea
- pupil constriction
- tolerance

Q: What are the opioid receptors and what are their characteristics?
A: They are generally involved in pain perception.

How does the activation and mechanism of action of opioid receptors work?

Q: What were challenges/goals of studying the SAR of morphine?
A: Goal: Identify compounds with the analgesic properties but without the side-effects.
Challenges: PK were challenging: Super hard to design a molecule that goes where you want it to.

Codeine:

Q: How was the crossing of the BBB improved from morphine?
A: - acetylation of the 6-OH increases analgesic properties of the drug by improved PK properties --> 6-OH is not part of the pharmacophore

Q: What is the difference between heroine and morphine and what effects does this have?
A: - both 3-OH and 6-OH are acetylated --> excellent crossing of the BBB
- effective analgesic only when the 3-acetyl group is hydrolysed --> its part of the pharmacophore
- severe tolerance and dependence

Q: What is the importance of the nitrogen in the morphine structure?
A: The charged nitrogen is very important for the binding activity and removing it reduces all reactivity! Also lowering its pKa already decreases/removes the activity.

Q: Considering the analgesic activities of morphine and its enantiomer, explain how the chirality of a drug can be important:
A: The enantiomer of morphine has no analgesic activities at all --> receptor seems to be chiral as well!

What are the general SAR relationships for morphine?

Starting from the structure of morphine:
What could be general metabolic products?

Q: How are analogues of morphine synthesised?
A: - the synthesis of morphine analogues was hindered by the complexity of the structure such that total synthesis is not possible as a source of the drug
- however analogues of morphine were synthesised by modification of the natural product

Q: What is the most common structural change for the synthesis of morphine analogues?
A: - change of the substituents on the nitrogen
- this is achieved by acylation and demethylation
- a mixture of agonistic and antagonistic effects was observed with N-alkylation

Q: In which cases can antagonists of morphine be used?
A: - one of them, Naltrexone, is an antagonist given to drug addicts: it blocks the euphoric effects
- the drugs can in general be used to treat morphine overdoses particularly where there is a danger of respiratory failure

Q: Which opioid receptor is responsible for the hallucinogenic side-effects?
A: - the sigma receptor

Agonism vs. antagonism and normal function of opioid receptors: Show the concepts in a scheme

What are the benzomorphans and what are they used for?

Q: What are phenylpiperidines and what are their properties?
A: - they are simplified analogues of morphine
- retain the addiction and respiratory depression side-effects
- are fast acting but have shorter duration
- they are easy to synthesise! :-)

Fentanyl --> 100-fold more active than morphine

Methadone:
- orally active and has less side effects than morhpine
- it is addictive, but it is given to drug addicts (I guess it's just not as addictive as other stuff)
- it has one chiral center: the R enantiomer is more active

Q: How was the constipation side-effect of morphine and it's analogues axploited?
A: Develop an analogue that doesn't cross the BBB, but activated the opioid receptors in the small intestine. Use this to treat diarrhea.

What are enkephalines?

Q: What are endogenous opioid peptides?
A: The different groups have selectivities for the different types of opioid receptors.

Q: How can the stability of the enkephalines be improved?
A: - the enkephalines are inactivated in vivo by peptidases
- their stability can be improved by replacement of the glycine groups with unnatural D-alanine and N-methylation

Q: What is neuropathic pain?
A: Neuropathic pain is caused by nerve damage and is difficult to treat.

Explain for the example of chronic neuropathic pain the stepts taken for target validation of P2X_3:

The general structure and idea is based on the enkephalines: the body's natural pain killers.

What is the most common mechanism of action for drugs treating depression?

What provided the basis of assays for analysis of compounds interacting with the neutrotransmitter receptors in the CNS?

Serotonin

In a scheme show the transmission process for neurotransmitters:

What were the early treatments of depression? What were the disadvantages?

What is the name and the general structure of the early drugs treating depression?

Q: What are neurotransmitter transporters?
A: - membrane bound and respond to signals outside the cell
- transport neurotransmitters, hormones, amino acids and carbohydrates in order to control their concentrations
- they are similar to ion channels; activated or inactivated by the ligand concentration

What was the hypothesis on Serotonin uptake as a therapeutic target and how was this analysed?

Q: What is a drawback of targeting Serotonin receptors?
A: There exists a very large number of Serotonin receptors in the body, which are expressed in different tissues --> big risk of side-effects

Q: What are three important targets in neurotransmitter signalling?
A: - the receptor
- the transporter
- monoamine metabolism

Q: How can monoamine metabolism be targeted?
A: --> goal is to increase neurotransmitter signalling

Q: What could the following structures be targeting?
A: --> increase serotonin signalling by inhibiting its metabolism --> anti-depressants

5-HT uptake inhibitors:
- increase serotonin neurotransmitter signalling by inhibiting its reuptake
- use as anti-depressants

Q: Explain with the example of Fluoxetine how the counter ion in a salt can have important effects:
A: - its a 5-HT reuptake inhibitor
- counterions can have a large effect on PK by changing the water solubility

Q: Different enantiomers of a drug, what are the usual observations/effects?
A: With the example of Fluoxetine:

Q: What is a general functionality often observed for drugs targeting neurotransmitter transporters?
A: Aryl-sulfonamides

Q: What is often done if a compound with f.ex. two stereocenters is a hit in HTS?
A: Reduce stereochemical complexity!

Q: What is a very selective way to inhibit a neurotransmitter transporter in the brain?
A: RNAi

What is the concept of polypharmacology?

What is inflammation?

What are the classical symptoms of inflammation?

What is the pathogenesis and symptoms of inflammation?

Q: What is the general mechanism of action of anti-inflammatory drugs?
A: There is a number of molecular mediators of acute inflammation such as cytokines and chemokines. Anti-inflammatory drugs inhibit synthesis, release and function of those mediators.

What are the four classes in which most anti-inflammatory drugs fall into?

Q: What are the general problems with acetyl salicylic acid?
A: The side effects however usually really just appear after taking it for a longer period of time.

What are prostaglandins and what are their general properties?

Q: What is the mechanism of action of acetyl salicylic acid?
A: - it inhibits prostaglandins --> blocks synthesis and release of an intermediate
- it acetylates serine 530 of cyclooxygenase and thus blocks the biosynthesis of the prostaglandins

Q: Eicosanoids: What are they and what do they do?
A: - one class of molecular mediators of acute inflammation
- are biosynthesised from arachidonic acid
- they elicit a variety of different pharmacological effects, mediated by different receptors and their effects are driven by their nature and tissue expression patterns

Q: What is the general target of non-steroidal antiinflammatory drugs (NSAID)?
A: They inhibit cylooxygenase in the arachidonic acid pathway:

Acetylsalicylic acid

What are the most expected metabolites of acetyl salicylic acid?

Q: COX-1 and COX-2 isoforms overlapping and distinct functions and thus different effects for selective inhibitors:
A: Crystal structures of the two enzymes were really a break through for medicinal chemistry here.

COX-2 inhibitors!

Q: Explain the difference between "on-target toxicity" and "off-target toxicity":
A: On-target-toxicity: inhibition of intended target in other tissues
Off-target toxicity: unintended inhibition of other biological targets

Explain in general by what side effects of drugs can be caused:

Q: Lipooxygenase in the Arachidonic acid pathway:
A: Important for the production of leukotrienes.

Q: Lipooxygenase:
A: It is important in the Biosynthesis of leukotrienes. Leukotrienes are also classical mediators of inflammation.

Q: What is a typical feature of inhibitors for 5-lipooxygenase:
A: N-hydroxy ureas

At which steps is the arachidonic acid pathway modulated and by which type of drugs?

What are steroid hormones and what are they and related compounds used for?

In which two classes are steroid hormones categorised?

Describe the superfamily of intracellular receptors:

What is the mechanism of class 1 steroid hormone receptors?

Q: What are the three general domains of the steroid hormone receptors?
A: 1. Ligand (steroid) binding domain
2. DNA binding domain
3. variable region: involved in transcription activation

General numbering system and basic structure of steroids.

These are common natural steroids!

How are steroid hormones normally biosynthesised and what are their general properties?

What is the biological activity of adrenal cortex hormones?

What are the therapeutic applications of steroid hormone drugs?

What are general side effects of steroid hormones?

What is the general mineralocorticoid activity?

What is the main aim of adrenocorticoid medicinal chemistry?

How has the glucocorticoid vs. mineralocorticoid receptor selectivity been achieved?

Q: What are aspects of consideration for the drug delivery of steroids?
A: C17 and C21 are often modified at their hydroxy groups to esters or elimination at C17.

Estrogens and their medical applications:

What are selective estrogen receptor modulators?

Estrogens and their importance in breast cancer:

What are progestins and what are they used for?

What are androgens ans what are they used for?

Q: What are androgen receptor antagonists usually used for?
A: The hydroxy group of hydroxyflutaminde should immediately be spotted as a likely result from metabolic action.

What are peroxisome proliferative-activated receptors and what are they important for?

Q: How are the side effects of steroids limited?
A: By use of local delivery and subtle structural changes.

What limits access to structural changes in steroids?

Q: What are viruses?
A: - non-cellular infectious agents which take over a host cell in order to survive and multiply
- viral epidemics and pandemics have been devastating for human populations

Q: How are viruses often transmitted?
A: - sneezing
- anthropods or ticks
- physical contact
- food

What are the differences between short and long latencies?

How are viruses built/ what are they made of?

How are viral infections usually treated and what is the desired way of treatment?

What is target selection for antiviral drugs? What needs to be considered and what can be potential drawbacks?

How do nucleoside inhibitors of DNA viruses work?

Q: Why are nucleoside triphosphates not useful as drugs and how can we still use them?
A: Use the precursor! Let the cells phosphorylate them on their own.

What is the nucleoside scaffold and where can it be found in nature?

What are the general properties of nucleoside drugs and especially their drawbacks?

What was the challenge with nucleoside inhibitors for medicinal chemists?

These are typical examples of nucleoside inhibitors for DNA viruses.

Q: What are the three general mechanisms of action of nucleoside drugs?
A: 1. Competitive inhibition of the viral polymerases
2. Chain termination mechanisms
3. Lethal mutagenesis mechanisms

Explain the three different chain termination mechanisms for nucleoside drugs:

Explain the mechanism of nucleoside drugs with lethal mutagenesis:

Acyclovir

Explain the mechanism of acyclovir and why it is selective to virus infected cells:

Analogues of acyclovir:

Why do the analogues of acyclovir: pencyclovir and famcyclovir show better oral bioavailability?

What are acyclic monophosphonates and what advantages do they have over the acyclovir analogues?

Acyclic monophosphonates as antivirals.

Q: What is a general problem with acyclic monophosphonates?
A: They often exhibit renal toxicity, which limits their applicable dosis.

Q: What is very difficult to predict in terms of activity of the acyclic monophosphonates?
A: It is very hard to predict against which viruses they will be actually active.

What are the characteristics of the Hepatitis B virus, especially of interest for medicinal chemistry?

An acyclic nucleoside analogue.

Q: How was the renal toxicity of adefovir adressed in a new generation of acyclic nucleoside drugs?
A: With pro-drug modifications that deliver the drug selectively to the liver:

Q: What can be very important for the development of antiviral drugs for a specific virus?
A: If you know the life-cycle of the virus you can predict and select a target that might inhibit the virus best.

Q: Explain with the example of Hepatitis C virus, how understanding the life cycle of a virus can result in very selective drugs:
A: Mechanism of action involves the formation of a covalent bond between the drug and the protease.

Explain with the example of the hepatitis C virus how a host miRNA can be important for viral replication and how this was used for the development of an antiviral:

Q: Describe the most important aspects of the influenza virus and explain how its is classified:
A: H = Hemaglutinin

Describe the most important aspects of the influenza virion architecture:

Describe the replication cycle of the influenza A virus:

Q: Why does the NA on the surface of the influenza A virus during viral budding cleave surface sialic acids?
A: Such that this virus particle doesn't just enter the same cell again!

What is the concept of antigenic drift?

What is the concept of antigenic shift?

What is the principle strategy against the flu?

What are the most important aspects of the flu vaccine?

Adamantane drugs that inhibit the M2 ion channel in the influenza virus.

Q: What are adamantane drugs and what are their drawbacks?
A: - early antiviral drugs, which inhibit the M2 ion channel of the influenza viru

What are the mechanisms of action of the adamantane drugs?

What is a very important feature of RNA viruses that was used for the design of broad-spectrum antivirals and which type of compounds was developed for this?

What is neuramidase (NA) and why is it a good drug target in influenza virus?

Q: Explain how the mechanism of neuraminidase was used to develop selective inhibitors:
A: Remember: Enzymes tend to bind the transition state with very very high affinity, much more than the substrate or the product.

Q: What do you need to do if you have a very polar lead compound which drastically lowers oral bioavailability?
A: Identify auxophoric groups and exchange them for apolar groups.

Give a short summary of the five targets of the influenza virus against which drugs have been developed:

What are the most important aspects of HIV infections?

What are the different HIV treatments at which states and what is the efficiency?

Give a short overview of the mechanism of viral replication of HIV and state its most important features:

Which are the five "low-risk" intervention points of HIV therapy?

What properties should HIV drugs have?

Q: How is resistance through mutation compated in the HIV virus?
A: Combination therapy: Give several drugs at once, which have different targets.

What are the drugs used for Highly active antiretroviral therapy (HAART)?

Q: Which types of compounds targets the reverse transcriptase of HIV?
A: Nucleoside inhibitors!

It acts against the HIV reverse transcriptase.

What are non-nucleosides targeting reverse transcriptase?

What is the HIV protease?

Q: What is the mechanism of HIV protease inhibitors?
A: They are generally transitionstate isosteres.
An enzyme binds the transition state usually with very high affinity.

What are examples of possible transition state isosteres for the HIV protease and what are their properties?

What is Saquinavir?

Q: What could be general strategies if the X-ray structure of an enzyme-inhibitor complex revelas a largely infilled sub-site?
A: Add large groups on parts of the drugs in vicinity of that sub-site. Depending on the nature of the subsite, choose polar or less polar modifications.

Q: What is Ritonavir and which property of the HIV protease was exploited, when designing this compound?
A: Ritonavir was then developed by modifications of these C2-symmetrical leads.

What does the symmetrical nature of an active site of an enzyme allow for?

Indinavir as an example for the combination of substructures in the case of a symmetrical enzyme binding site:

What are the important aspects of HIV and drug resistance? How can it be prevented?

Q: Inhibition of the host cell receptors as a treatment for HIV, why ist it possible?
A: Unfortunately, also resistances have come up, where the virus has mutated it's envelope protein such that it is able to bind to the receptor with the drug in place!

Inhibitor of the CCR5 receptor as a treatment for HIV.

Mechanism of action of enfuvirtide:

Fuzeon (Enfuvirtide): Inhibitor of HIV cell entry.

What are the two main groups of protein kinases?

What are key aspects and characteristics of kinases?

What are kinase-linked receptors and what are their properties?

Q: How was kinase medicinal chemistry immensly expanded and why was that a surprising thing?
A: - it was long thought that kinases are not ideal drug targets or especially not the ATP binding site, as it has to be similar in all kinases, since they all bind ATP and thus specificity and off-target toxicity might be a problem
- however, crystal structures have shown that the ATP binding site varies considerably, allowing selectivity for drugs which bind

EGFR and its importance in disease:

What could be possible metabolic problems for the following drug structure and how could they be circumvented?

What exactly is the BCR-ABL kinase?

It inhibits BCR-ABL.

Q: What are the two drwabacks of having a very flexible drug?
A: 1. The drug binds in only one conformation, so if it is very flexible, binding is entropically disfavoured
2. The more flexible a drug is, the more likely it will interact with more than one target and produce toxicity

What are the type I, II and III kinase inhibitors?

What is drug resistance?

How does drug resistance arise in connection with cancer?

What mechanisms except mutation have been identified with Imatinib?

Q: How was resistance by mutation to imatinib treated?
A: A new generation of inhibitors, which are able to target the mutated forms of the kinase.

What is off-target or mechanism independent toxicity and how has it been exploited in the cancer treatment?

What is one of the clear distinguishing features of biologicals in terms of toxicity?

Q: What other class of very specific kinase inhibitors have been developed?
A: Monoclonal antibodies targeting kinase receptors have been developed as anticancer drugs.

Cardiotoxicity of receptor kinase inhibitors:

Why is identification of the cause of toxicity very important for a certain drug (in the context of receptor kinase inhibitors)?

How is toxicity testing usually carried out?

How can selectivity of kinase inhibitors be identified?

What is AML?

Quizartinib: A kinase inhibitor used for the treatment of acute myeloid leukemia

Why is FLT3 a good target for the treatment of AML?

Applications of kinase inhibitor drugs today: Three main categories

What is the role of medicinal chemistry and what is the key to success?

Q: On what does rational target selection depend?
A: On understanding the mechanism of disease.

Q: How is nature able to target "undrugable sites"?
A: These structures are way too complex for what is desired by a medicinal chemist --> they want easy structures that can be manufactured "cheaply" on a large scale.

Q: How are drugs usually based on natural products?
A: Work backwards: Make a complex molecule simpler but keep the activity.

In a sentence descirbe electrostatic interactions:

Q: Which five are the most important types of interactions between drugs and their targets?
A: 1. Electrostatic interactions
2. H-bonds
3. Charge-transfer complexes
4. Hydrophobic interactions
5. Van der Waals interactions

Explain H-bonds in one sentence:

Explain charge-transfer complexes in one seltence:

Explain hydrophobic interactions in one sentence:

Explain van der Waals interactions in one sentence:

How are leads typically identified?

What are important tools used for lead optimisation?

What are the three most important PK properties of a good drug?

What are important aspects in lead optimisation in terms of PK?

What is a very important consideration for amino- and carboxylate groups in terms of PK?

What are the five characteristics of a drug candidate as the output of medicinal chemistry? What are the next steps to be taken with that candidate?