IMC 09: Drug Discovery and Development

Question 1

Pharmacodynamics

What is target inhibition?

Answer 1

blocking the activity of the biological binding partner for the drug/inhibitor

Question 2

Pharmacodynamics

What are on-target effects?

Answer 2

pharmacologic effects caused by a drug interacting with its intended biological target

Question 3

Pharmacodynamics

What are off-target effects?

Answer 3

pharmacologic effects caused by a drug, but not due to binding of its intended biological target

Question 4

How are most new drugs produced (the processes)?

Answer 4

from high-throughput screening and subsequent optimization

Question 5

What is high-throughput screening?

Answer 5

vast libraries of chemical compounds can be screened in high-throughput assays to identify inhibitors that may have therapeutic benefit

Question 6

What is an assay?

Answer 6

analysis of the biochemical/biological potency of a chemical species

Question 7

What are targeted assays/screens?

Answer 7

seek agents that bind to a specific biological target (protein) to alter its function

• typically done in a biochemical (cell-free) setting

Question 8

What are phenotypic assays/screens?

Answer 8

seek agents that induce a particular biological effect in a model system

• may be in a cellular assay, animal model, or other biological setting

Question 9

What are the steps of the drug discovery and development process?

Answer 9

• target validation
• hit identification and optimization
• clinical candidate
• clinical testing – phase I-III
• FDA approval

Question 10

What is target validation?

Answer 10

identify promising strategies for drug intervention

• will a drug against this target have the desired therapeutic effect
• may include identifying a single protein target, targeting a process or pathway, using a disease model, etc.

Question 11

What is hit-to-lead development?

Answer 11

transform compounds from screening ‘hits’ into promising candidates for clinical testing (leads)

• role of medicinal chemists

Question 12

What is a hit compound?

Answer 12

chemical compound that shows promising activity in a high-throughput screen, but has not been chemical optimized using medicinal chemistry

• represent starting points for medicinal chemistry studies

Question 13

What is hit expansion?

Answer 13

helps identify functional groups on a hit compound that could be modified to improve activity

• modify molecule in different directions

Question 14

What is a lead compound?

Answer 14

chemically optimized compound that has high affinity for its target and displays favourable activity in cells and pharmacokinetic models

Question 15

What is a clinical candidate?

Answer 15

compound ready for clinical testing, with optimized efficacy and safety testing in animal models

Question 16

What are structure-activity relationship (SAR) studies?

Answer 16

how changes to the chemical structure of a molecule affect its activity

• can also introduce modifications that alter other properties of a drug molecule: decrease undesired binding to other proteins, increase metabolic stability, decrease toxicity, improve solubility, improve membrane permeability
• balancing drug potency with other parameters such as metabolic stability, selectivity, and biological activity can be challenging
• studies entail several rounds of modifications on multiple sites of a compound

Question 17

Rotatable Bonds

Answer 17

–

Question 18

Identify the strategies that can be used to improve the activity and efficacy of drug molecules.

Answer 18

structural modifications

• hydrophobic expansion
• isosteric replacement

in silico modelling and co-crystal structures

Question 19

What is hydrophobic expansion?

Answer 19

increasing hydrophobic attachment (chain length) to increase compound’s activity

• enzyme active sites are generally hydrophobic compared to the surrounding environment
• medicinal chemists can probe for hydrophobic interactions by increasing alkyl chain length – this also changes physicochemical properties of the drug molecule including solubility and logP

Question 20

What is isosteric replacement?

Answer 20

switching out different isosteres can alter drug activity and change physicochemical properties

Question 21

What is an isostere?

Answer 21

chemical group that can approximate the physical and chemical properties of another chemical group

• isostere is a more specific term than mimetic – mimetic may refer to the entire drug molecule, whereas isostere would refer to a specific group

Question 22

What is a classical isostere?

Answer 22

two comparable groups with the same valency (number of attachment points)

Question 23

What is a bioisostere?

Answer 23

chemical group that can replace another chemical group without (significantly) affecting the biological activity of the drug

• are typically less than exact structural mimetics, and are often more alike in biological rather than physical properties – therefore an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance

Question 24

In Silico Modelling and Co-Crystal Structures

What are protein-ligand docking strategies?

Answer 24

aim to position chemical compounds into a binding site on a protein and evaluate the strength of interaction (computer program)

• designed compounds within hit-to-lead development stages can also be docked prior to their synthesis

Question 25

In Silico Modelling and Co-Crystal Structures

What is in silico screening?

Answer 25

massive libraries of chemical structures (> 1 million compounds) can be quickly screened for interactions with protein crystal structures, using several different software options

• hit compounds from in silico screening campaigns must be validated in biochemical and cell-based assays

Question 26

In Silico Modelling and Co-Crystal Structures

What can protein crystal structures show?

Answer 26

what part of the drug molecule sticks out of the active site (hydrophobic)

• one part of active site is exposed to water, solvent, etc. in cell – where most polar or charged part of inhibitor will be
• changing hydrophobic group exposed to water (ie. neutral at physiological pH) to hydrophilic group (ie. charged at physiological pH) increases activity – better interaction

Question 27

What is topological polar surface area (TPSA)?

Answer 27

calculated term representing the sum of the exposed areas of HBDs and HBAs of a molecule

• generally increases proportionally with molecular weight – therefore TPSA and 500 g/mol cut off by Lipinksi’s RO5 represent similar measurements
• highly related to HBD and HBA count

Question 28

What is the Easson-Stedman 3-point attachment hypothesis?

Answer 28

if a chiral compound interacts with 3 sites on a protein, the more potent enantiomer will be involved in three intermolecular interactions whereas the less potent enantiomer will only interact with a maximum of two sites

• if you have two enantiomers with 3 attachment points to a protein, one enantiomer/isomer will be more potent than the other – cannot fit the mirror image on the same interaction points

Question 29

How can a chiral molecule have the same activity as its chiral isomer (breaks the Easson-Stedman 3-point attachment hypothesis)?

Answer 29

only if it makes 3 attachment points

• if it only makes 2, can have the same interaction with its mirror image