Lecture 5.1

Question 1

What does the process of ‘hits-to-leads’ rely on?

Answer 1

1. availability of compounds
   –> quality (e.g. purity)
   –> diversity (e.g. structural diversity)
2. Effective assay system

Question 2

What are the sources of chemical diversity in identifying hits?

Answer 2

1. natural products
   –> plants
   –> marine organisms
   –> fermentation, microbial, animal
2. Biotechnology (proteins/ nucleic acids)
3. Synthesised compounds

Question 3

How are synthesised compounds ‘synthesised’?

Answer 3

1. rational approach
   –> based on x-ray diffraction of the biological target
2. chemical modification of existing
   compounds/pharmacophores

Question 4

What are the sources of compounds for compound libraries?

Answer 4

1. isolated natural products from microbes, plants or animals
2. collections of discreetly synthesized compounds –> focused around pharmacophores
3. random libraries –> combinatorial libraries

Question 5

What are pharmacophores?

Answer 5

structural features needed to activate or inhibit specific receptors or enzyme active sites

Question 6

How are combinatorial libraries made?

Answer 6

• Focus on molecules or pharmacophores with known biological activity
• Random selection of diverse representatives

Question 7

What kinds of chemical libraries are desired in drug discovery?

Answer 7

1. high degree of chemical diversity
2. compounds are present in sufficient quantity and quality

Question 8

What is the role of chemists in drug discovery?

Answer 8

After validating hits, optimize efficacy and pharmaceutical properties; structure based inhibitor design

Question 9

Apart from designing and synthesising a potential drug, what else does drug discovery process entail?

Answer 9

development of testing methods that are needed in the studies of how the molecule operates in the body.

Question 10

What is medicinal chemistry?

Answer 10

blends synthetic chemistry
natural product chemistry,
molecular modelling,
computational biology,
structural genomics, and
pharmacology to design and discover drug molecules for targets/diseases of
interest.

Question 11

What was the 1st rational development of a synthetic drug?

Answer 11

Arsphemamine (Salvarsan) with antiprotozoal effect

–> curing syphilis

–> developed by combining synthesis with biological screening and evaluation procedure

Question 12

What is a ‘lead compound’?

Answer 12

The compound on which a development is based

Question 13

What is meant by analogues?

Answer 13

Synthetic compounds developed from a lead are referred to as its analogues

Question 14

What does a Structure-activity relationship (SAR) study consist of?

Answer 14

synthesizing and testing a series of structurally related compounds to reveal the relative usefulness of different compounds

Question 15

What is Quantitative structure-activity relationships (QSAR) study?

Answer 15

quantitatively correlate the chemical structure of compounds to biological actions using mathematical models.

Question 16

What is the significance of Quantitative structure-activity relationships (QSAR) study?

Answer 16

The mathematical expression can then be used to predict the biological response of other chemical structures

Question 17

Many drugs have structures resembling
the ____________ of the drug targets.

Answer 17

endogenous ligands

Question 18

What approach of drug discovery cannot be applied to orphan receptors?

Answer 18

Modifying the structure of the
endogenous ligand

–> cannot be applied for orphan receptors

Question 19

What is the random (irrational) approach of drug discovery?

Answer 19

Scan thousands of potential compounds from natural sources for a hit against specific assays

Question 20

Describe the rational approaches in drug discovery.

Answer 20

determining the structure of the target (e.g. x-ray crystallography)
–> designing a drug to fit the target

Question 21

What are some modern technologies used for drug design?

Answer 21

1. Computer-based Drug Design (CBDD)
2. Structure-Based Drug Design (SBDD)

Question 22

What is meant by descriptors in drug discovery?

Answer 22

quantitative representations of molecular properties that are used to characterize the chemical structure of molecules

–> 1D, 2D and 3D

Question 23

What are 1D descriptors?

Answer 23

simple property counts
–> polar surface area
–> MW
–> polarisability
–> H-bond doner
–> rings

Question 24

What are 2D descriptors?

Answer 24

represented by substructure or fingerprints accounting for the presence or absence of particular features

Question 25

What are 3D descriptors?

Answer 25

take into account the conformational freedom of the compound encoded as a pharmacophore, 3D fingerprint, shape or field.

Question 26

Describe how in silico identification could be used in drug discovery.

Answer 26

1. screen database of commercially available compounds for 2D fingerprint similarity to template of receptor agonist 2. identify hits, confirm experimentally in an in vitro assay

Question 27

What recent advances has led to the possibility of virtual (in silico) screening?

Answer 27

1. computing power 2. high resolution structural determination by x-ray crystallography and NMR 3. Availability of sophisticated algorithms --> interactions of ligands and receptors

Question 28

Virtual (in Silico) screening of compounds can be conducted through:

Answer 28

1. Physical molecular properties 2. Chemical property --> number of H-bond acceptors or donors 3. Solvation parameters or chemical functionality of a binding pocket of the target protein

Question 29

What are the advantages of using in silico screening for rational drug design?

Answer 29

1. Filter out the majority of compounds that have little chance of hitting a target 2. Reduce the number of compounds being screened in bench-top assays

Question 30

What do static virtual libraries contain?

Answer 30

all virtual molecules that may exist within a certain set of boundaries.

Question 31

What is 'structure guided lead optimization'?

Answer 31

only those molecules that are predicted to bind to the target protein are synthesized and tested in the assays. --> in silico modelling of protein-ligand interactions

Question 32

What are dynamic virtual libraries?

Answer 32

contain virtual compounds that are relevant to the user’s research question. --> emphasis on assuring synthetic feasibility

Question 33

What is the emphasis of dynamic virtual libraries?

Answer 33

on assuring synthetic feasibility

Question 34

What does Lipinski's rule of five state?

Answer 34

It states that poor absorption or permeability are more likely when certain conditions are met

Question 35

Lipinski’s Rule of Five states that poor absorption or permeability are more likely when:

Answer 35

- cLogP > 5 - Molecular mass > 500 daltons (Da) - No of H-bond donors (OH +NH) > 5 - No of H-bond acceptors (O+N) > 5

Question 36

Which of the rule of 5 is changing less appreciably?

Answer 36

cLogP drug lipophilicity is changing less over time than other physical properties

Question 37

What is cLogP and what is it a measure of?

Answer 37

Calculated Log of the octanol-water partition coefficient --> a measure of a drug’s lipophilicity.

Question 38

What happens when the lipophilicity of a proposed drug is too high?

Answer 38

-increased likelihood of binding to multiple targets --> toxic -poor solubility and metabolic clearance

Question 39

How is cLogP defined?

Answer 39

ratio of un-ionized drug distributed between the octanol and water phases at equilibrium

Question 40

Higher values of cLogP imply greater _______________ .

Answer 40

lipophilicity

Question 41

Increasing lipophilicity will also tend to increase binding affinity. True or false.

Answer 41

True. Because the target site is often hydrophobic in nature.

Question 42

What are prodrugs?

Answer 42

Prodrugs are compounds that are biologically inactive but can be metabolized to an active metabolite

Question 43

What are some reasons of designing prodrugs?

Answer 43

- to enhance absorption - improve patient acceptance - reduce toxicity - slow release of drugs in body - achieve site specificity (only release drug in the vicinity of its site of action)

Question 44

What can prodrugs be classified into?

Answer 44

- bioprecursor prodrugs - carrier prodrugs

Question 45

What are bioprecursor prodrugs?

Answer 45

contain the embryo of the active species within their structure --> active species liberated through metabolism

Question 46

What are carrier prodrugs?

Answer 46

combining an active drug with a carrier species to form a compound with the desired characteristics

Question 47

Give an example of a carrier in carrier prodrugs?

Answer 47

a lipophilic moiety to improve transport through membranes

Question 48

What are the 2 carrier prodrug systems?

Answer 48

1. bipartate prodrug system 2. tripartate prodrug system

Question 49

What is bipartate prodrug system?

Answer 49

active species linked to the carrier by forming a functional group (e.g., amide, ester)

Question 50

What is tripartate prodrug system?

Answer 50

active species linked to the carrier by a link consisting of a separate structure.

Question 51

The lipophilicity of a drug can be improved by combining a lipophilic carrier with the polar group(s) on the drug so as to improve absorption and transport through membranes. True or false

Answer 51

True

Question 52

How can the water solubility of a drug be improved?

Answer 52

by introducing a carrier with a water solubilizing group(s).

Question 53

What carriers are used to from prodrugs so as to improve taste of drugs?

Answer 53

palmitic acid and other long chain fatty acids

Question 54

How can the duration of action of drug be prolonged? What carrier to use?

Answer 54

Slow hydrolysis of amide and ester linked fatty acid carriers

Question 55

Name a drug for which the toxic side effects were reduced by designing an appropriate prodrug

Answer 55

Salicylic acid cause gastric irritation and bleeding solution --> acetylated salicylic acid (aspirin) --> improve absorption and less irritation

Question 56

What kind of prodrug carrier are designed to cross blood-brain barrier (BBB) to achieve site specificity?

Answer 56

dihydropyridine ring system-based carriers

Question 57

Why are dihydropyridine ring system-based carriers appropriate for crossing BBB?

Answer 57

1. ring system has the required lipophilic character for crossing BBB 2. ring system can be synthetically modified to allow the link between the carrier and the drug 3. Once the prodrug crosses the BBB, the dihydropyridine can be easily oxidized by oxidases in the brain 4. The resulting hydrophilic quaternary ammonium salt cannot return across the barrier and is relatively nontoxic