Drug Design

Question 1

What is a drug target? (1)

Answer 1

• Key molecule involved in a metabolic or signalling pathway specific to a disease, condition or pathology

Question 2

Examples of drug targets (6)

Answer 2

• Enzymes (majority, protein kinases are most common due to druggability)
• Receptors (most are proteins)
• Carrier and structural proteins
• Nucleic acids
• Lipids
• Carbohydrates

Question 3

What the different approaches to drug discovery? (2)

Answer 3

• Ligand based
• Target based

Question 4

Ligand based approach (4)

Answer 4

• Indirect
• No knowledge about target, often serendipitous
• Observing phenotypic effects of substances on humans or animals, identifies agents that induce a desired phenotypic outcome
• Majority of small molecule first in class NMEs were discovered using phenotypic assays

Question 5

Aspirin (Ligand based approach) (6)

Answer 5

• Willow bark salicin extracted in 1840
• Structure investigated
• Salicylic acid synthesised (effective but irritant)
• Sodium salicylate made (non-irritant, awful taste)
• Analogues synthesised, tested on researcher’s father
• Aspirin emerged, MOA became known 1970s

Question 6

Target based approach (5)

Answer 6

• Direct
• Serial testing of substances with an isolated biological target in order to identify agents that induce a desired biochemical outcome
• More mechanistic approach to R&D
• Led to 17 of 50 first in class small molecule NMEs
• Elucidates 3D structure, provides detailed info about binding site and interaction with ligand

Question 7

What is hit-to-lead identification? What is the goal? (4)

Answer 7

• Purpose: improve the potency, selectivity and physicochemical properties (e.g. solubility and stability) of the compounds for further in vitro and in vivo testing and for subsequent lead optimization
• Hit discovery – employs high throughput screening (HTS) using cell-based or enzymatic screens to identify hit molecule (molecule that has desired activity determined by assay parameters)
• Hit-to-lead development: Cellular mechanism of action
• Lead optimisation aims to maximise the interactions of a drug with its target binding site in order to improve activity, selectivity and to minimise side effects

Question 8

How can we optimise a lead compound? (2)

Answer 8

• Drug optimisation can be achieved by different strategies or approaches on the lead compound SAR, such as: Variation of substituents, Extension of structure by isosteres and bio isosteres, Simplification of the structure
• Structure-based drug design makes use of X-ray crystallography and computer-based molecular modelling to study how a lead compound and its analogues bind to a target binding site

Question 9

Preclinical Testing (4)

Answer 9

• Evaluates aspects of PD/PK and toxicology in in vitro and in vivo settings
• In vitro on cell cultures, in vivo on mice
• PD establishes therapeutic index of drug
• PK describes changes in plasma concentration as a consequence of ADME

Question 10

In vivo testing (3)

Answer 10

• Results are more specific and detailed
• Usually follow in vitro testing as in vivo can capture the inherent complexity of organ systems and the internal environment of the human body, and account for interactions between various body procedures and cellular biochemistry
• Develop new treatments and research protocols

Question 11

In vitro testing (4)

Answer 11

• Uses cells derived from animals or cell lines, which have an infinite lifespan.
• Hence, these model systems are relatively cheap, simple to procure, and efficient
• Results are rapid
• Develop new treatments and research protocols

Question 12

What is a pharmacophore? (3)

Answer 12

• Which parts of molecule are important to biological activity? Which functional groups are important to binding to receptor?
• An abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule
• Summarises the important binding groups that are required for activity

Question 13

What is a receptor? (2)

Answer 13

• Specialised target macromolecule that is present on cell surface or intracellularly that binds drug and mediates its pharmacological actions
• Drug response depends on its affinity (strength of binding) and efficacy (degree to which it induces desired response)

Question 14

What is an orphan receptor? (2)

Answer 14

• Proteins that bind and are activated by hitherto unknown signalling molecules (called ligands, neurotransmitters, or hormones).
• However, they share structural components with identified receptors whose signalling molecules are already known.

Question 14

What is an orphan receptor? (2)

Answer 14

• Proteins that bind and are activated by hitherto unknown signalling molecules (called ligands, neurotransmitters, or hormones).
• However, they share structural components with identified receptors whose signalling molecules are already known.

Question 15

What are the different classifications of drugs? (2)

Answer 15

• Based on their primary biological effects - psychopharmaceutical agents acting on CNS, pharmacodynamic agents, chemotherapeutic agents, metabolic agents
• Basis of classification of drugs – pharmacological effects, biochemical process they affect, chemical structure, molecular target (most useful)

Question 16

Typical properties of a small molecule drug (3)

Answer 16

• Low molecular weight organic compound (<900 Daltons) that may help regulate a biological process
• Low molecular weights allow possible rapid diffusion across cell membranes in order to reach intracellular sites of action
• Aspirin is a small molecular drug (180 Daltons) is now used for wide range of indications including Alzheimer’s, cancer therapy, pulmonary disease, and everyday aches and pains

Question 17

Why do small molecule drugs continue to dominate? (4)

Answer 17

• They lump together many molecules who do not necessarily share the same structure, function, medical use, potency, safety profiles
• Our biology is driven by small molecules e.g., cAMP
• Relatively easy to make
• Cheaper than biologics ($1 a day vs $22 a day)

Question 18

Define potency (3)

Answer 18

• The amount of drug needed to produce an observable effect
• Limited clinical significance can be actually obtained from the potency.
• It is only useful for drug selection if the potency of a drug is so small that a very large dose must be given for any response, so large that it becomes burdensome for the patient to take

Question 19

Define efficacy and how it affects the dose response curve (4)

Answer 19

• The maximum effect that a drug can induce on the tested subjects irrespective of concentration
• The steepness of the dose response curve can illustrate the efficacy of the drug
• Efficacy is one of the main characteristics for consideration of prescription drugs.
• The curve helps determine the therapeutic beneficial effects, dosage, and frequency of a drug as well as safety or hazard levels of drugs

Question 20

IC50 (1)

Answer 20

• The drug concentration causing 50% inhibition of desired activity

Question 21

GI50 (1)

Answer 21

• The concentration for 50% of maximal inhibition of cell proliferation

Question 22

ED50 (1)

Answer 22

• the concentration causing 50% of maximum effect for any measured biological effect of interest

Question 23

LD50 (1)

Answer 23

• The concentration causing 50% cell death (LD = Lethal Dose)

Question 24

What are agonists and types of agonists? (4)

Answer 24

• Drug that binds to receptor, producing a similar response to the intended chemical and receptor
• Complete agonist
• Partial agonist
• Inverse agonist

Question 25

What is a complete agonist? (1)

Answer 25

• bind directly to receptor at the same binding site where natural ligands bind, therefore bringing about a faster response

Question 26

What is a partial agonist? (1)

Answer 26

• indirect, promote the binding of the natural ligand to receptor site, produce a delayed response

Question 27

What is an inverse agonist? (1)

Answer 27

• produces opposite effect by binding to a receptor, decreases receptor’s activity below the baseline

Question 28

What is an antagonist and types of antagonist? (4)

Answer 28

• drug that binds to the receptor either on the primary site, or on another site, which all together stops the receptor from producing a response
• Competitive antagonist
• Non-competitive antagonist
• Irreversible antagonist

Question 29

Competitive antagonist (1)

Answer 29

• drugs that bind at the same binding site of receptor and prevent the natural ligand from binding

Question 30

Non-competitive antagonist (1)

Answer 30

• binds at an allosteric site, causes a conformational change in the receptor, prevents natural ligand from binding

Question 31

Irreversible antagonist (1)

Answer 31

• bind strongly to receptor through covalent bonds and cannot be displaced or washed out, permanently modifies receptor and prevents binding of natural ligand

Question 32

What effect do agonists and antagonists have on a dose response curve in terms of potency and efficacy? (2)

Answer 32

• Maximum potency of agonist remains unchanged in presence of competitive antagonist, efficacy of agonist decreases
• Maximum potency of agonist decreases in presence of non-competitive antagonist