Lecture 1: Drug Invention and the Pharmaceutical Industry

Question 1

Refers to the ease with which the function of a target can be altered in the desired fashion by a small organic molecule

Answer 1

Drugability (of a target)

Question 2

Favorable characteristics for drugability

Answer 2

1. small molecule
2. affinity to binding site
3. a well-defined binding site
4. binding to numerous binding sites

Question 3

What phase of clinical trials does the patient recieve the experimental drug

Respondents used are ‘patients’ of the disease

Answer 3

Phase II and III

Question 4

Before drug is approved for sale, what must be proven?

Answer 4

(Phase III)
Efficacy and adequate margin of safety

Question 5

Type of trial that requires experimentation of at least two kinds of animals - rodent and non rodent

Answer 5

Preclinical Trials

Question 6

Before administering to people, a potential drug or compound is evaluated for:

Answer 6

1. carcinogenicity
2. genotoxicity
3. reproductive toxicity

Question 7

Caffeine Discovery

Answer 7

When it was observed that goats became frisky and gamboled at night after eating berries or the coffee plant

Question 8

Belladonna (“beautiful lady”)

Answer 8

Used as eyedrops to dilate pupils - making them bigger

seen as attractive

Question 9

Morphine discovery

Answer 9

from poppy juice containing opium

Question 10

Postulated the existnece of chemical receptors in tissues that interacted with and “fixed” dyes

• invented arsphenamine (1907) aka salvarsan - as organic arsenicals for antimicrobial of syphilis

Answer 10

Paul Ehrlich

Question 11

Created prontosil - the first clinically useful sulfonamide to treat streptococcal infections

(also dye based)

Answer 11

Gerhard Domagk

Question 12

True or False

Most drugs were small organic molecules (typically <500 Da)

before recombinant DNA technology

Answer 12

True

Question 13

Usual approach to the invention of small molecule drug

Answer 13

library screening (collection of chemicals) for compounds with desired features

High-throughput screening of libraries containing hundreds of thousands to millions of compounds for their capacity to nteract with a specific molecular target or elicit a specific biological response

Alternative approach: determine a substance with known desired features and synthesize or focus on close chemical relatives

Question 14

Ideal target molecules

Answer 14

of human origin obtained by transcription and translation of the cloned human gene

Question 15

‘Hits’ or potential drug

Answer 15

chemicals known to react with the human protein and not just with its relative (ortholog) obtained from mouse or other species

Question 16

Which is more difficult to obtain hits? (A or B)

A. protein target has a well-defined binding site for a small molecule
B. the goal is to employ a small molecule to mimic or disrupt the interaction between two proteins

Answer 16

B

Question 17

() synthesize derivatives of hits to define the structure-activity relationship and optimizing parameters (ex. affinity for the target, agonist/antagonist activity, permeability across cell membranes, absorption and distribution in the body, metabolism, and unwanted effects)

Answer 17

Medical Chemists

Question 18

Method that offers the most detailed structural information if the target protein can be crystallized with the lead drug bound to it

Answer 18

x-ray crystallograpy

coupled with molecular modelling and computational chemistry, the structure provides the chemist with information about substitutions likely to improve the “fit” of the drug with the target (to enhance affinity of the drug for its target)

Question 19

Method that also studies drug-receptor complex but has lower resolution

Advantage is that the complex need not be crystallized

Answer 19

Nuclear Magnetic Resonance (NMR)

Question 20

NMR

Answer 20

Nuclear Magnetic Resonance

Question 21

Goal of computational approach to hits

Answer 21

1. determine hit with a high affinity to bind to the desired target
2. determine high affinity of the hit to other non-target human proteins to predict possible unwanted effects
3. pharmacodynamics of the hit binding to the target
4. pharmacokinetics

Question 22

Large molecule drugs

Answer 22

• Proteins (ex. insulin, growth hormone, )
• antisense oligonucleotides & siRNAs - used to block gene transcription or translation
• monoclonal antibodies

Question 23

Type of drug

• should be administered parenterally (modes the bypass GIT - IV, IM, SC, ID injections)
• targets must be accessed extracellularly

Answer 23

Protein drugs

• proteins that pass the GIT are digested and cannot be utilized for the intended drug function
• proteins cannot diffuse through the cell membrane - interaction must be extracellular

Question 24

Modern Drug Invention begins with

Answer 24

Determination of the Target
a statement (or hypothesis) that a certain protein or pathway plays a critical role in the pathogenesis of a certain disease, and that altering the protein’s activity would be effective against that disease

Question 25

Crucial Questions in modern drug invention:

Answer 25

1. **Is the target drugable** - can one find a drug that will have the desired effect against its target? 2. **Has the target been validated** - does modulation of the target protein affect the course of disease? 3. **Is this drug Invention effort economically viable** - does this project make sense economically?

Question 26

# True or False Intracellular targets are intrinsically easier to approach, and, in general, only intracellular targets are accessible to macromolecular drugs

Answer 26

False ## Footnote **Extracellular** targets are intrinsically easier to approach, and, in general, only **Extracellular** targets are accessible to macromolecular drugs

Question 27

# True or False If the target is an enzyme or a receptor for a small ligand, one is encouraged. If the target is related to another protein that is known to have a binding site for a regulatory ligand - one is hopeful If the known ligands are large peptides or proteins eith an extensive set of contacts with their receptor - the challenge is much greater If the goal is to disrupt interactions between two proteins, it may be necessary to find a "hot spot" that is crucial for the protein-protein interaction, such a region may not be detected

Answer 27

True

Question 28

Accepted target validation protocol

Answer 28

* If disruption of the gene encoding a specific enzyme or receptor has a beneficial effect in a valid murine model of a human disease, then potential drug target is validated * human mutations

Question 29

Loss-of-function mutation in *PCSK9* gene

Answer 29

lowered LDL cholesterol concentrations in blood > reduce risk of myocardial infarction ## Footnote **Target**: PCSK9 gene **Action**: loss of function for the target **Drug**: antibodies that inhibit the action of PCSK9

Question 29

Loss-of-function mutation in *PCSK9* gene

Answer 29

lowered LDL cholesterol concentrations in blood > reduce risk of myocardial infarction ## Footnote **Target**: PCSK9 gene **Action**: loss of function for the target **Drug**: antibodies that inhibit the action of PCSK9

Question 30

# True or False Funds to invent drugs targeting rare diseases or diseases primarily affecting developing countries (ie. parasitic diseases) often come from taxpayers or wealthy philanthropists

Answer 30

True ## Footnote Investor-owned companies do not develop drugs for these diseases. This is because, since they are rare or are in underdeveloped countries, it will not have the desired profit or the revenue needed to repay R&D and production costs

Question 31

# What part of the Drug development process: * consider all aspects of the molecule - its affinity and selectivity for interaction with the target; its pharmacokinetic properties (ADME); issues of its large scale synthesis or purification; its pharmaceutical properties (stability, solubility, questions of formulation); and its safety * modifies molecule or changes the way molecule is presented for use * testing for general toxicity by long-term monitoring of the activity in **2 species of animals** * compounds evaluated for **carcinogenicity, genotoxicity, and reproductive toxicity**

Answer 31

Preclinical Research

Question 32

What are the 2 animal species generally used for preclinical research

Answer 32

(1) rodent: mouse (2) non-rodent: rabbit

Question 33

What is used when possible to spare animals and to minimize costs in preclinical research

Answer 33

Invitro and Invivo assays

Question 34

If unwanted effects are observed in preclinical trials, what are the possible sources

Answer 34

1) mechanism based (caused by interaction of drug to the intended target) 2) off target effect (can be minimized by further optimization of molecule)

Question 35

Next step before a drug candidate can be administered to human subjects in a clinical trial

Answer 35

Filing of a IND (Investigational New Drug) Application

Question 36

A request for permission to use the drug for human research

Answer 36

IND Application ## Footnote Contains 1. rationale of the drug 2. preliminary evidence of efficacy in experimental systems 3. pharmacology 4. toxicology 5. chemistry 6. manufacturing 7. plan for investigating the drug in human subjects

Question 37

# True or False The FDA has **30 days** to review the IND application, by which time the agency may disapprove it, ask for more data, or allow initial clinical testing to proceed

Answer 37

True

Question 38

Requirement for FDA approval of drugs

Answer 38

1. proof of efficacy 2. safety in terms of the risk-to-benefit ration