Drug Discovery and Design

Question 1

What is pharamacognosy?

Answer 1

The study of the physical, chemical, biochemical, and biological properties of drugs, drug substances, or potential drug substances of natural origin, as well as the search for new drugs from natural sources.

Question 2

What are secondary metabolites (also known as natural product)?

Answer 2

• Not essential for survival (no intrinsic function)
• Species specific
• May provide a competitive survival benefit to producing organism

Question 3

What is Lipinski’s rule of 5 pertaining to oral compounds?

Answer 3

Its molecular weight is less than 500.

The compound’s lipophilicity, expressed as a quantity known as LogP (the logarithm of the partition coefficient between water and 1-octanol), is less than 5.

The number of groups in the molecule that can donate hydrogen atoms to hydrogen bonds (usually the sum of hydroxyl and amine groups in a drug molecule) is less than 5.

The number of groups that can accept hydrogen atoms to form hydrogen bonds (estimated by the sum of oxygen and nitrogen atoms) is less than 10.

Question 4

What are the Perceived Disadvantages of Natural Products?

Answer 4

access and supply

inherent slowness of natural product research

intellectual property rights

hopes for combinatorial chemistry banks/libraries

Question 5

What is Combinatorial Chemistry?

Answer 5

• rapidly creates large numbers of structurally similar molecules, under the same conditions, all at the same time

• larger, more diverse compound libraries “combinatorial
library”

Question 6

What other discovery compound method deals with knowledge of drug receptors to design or identify a lead?

Answer 6

Rational drug design

Question 7

SAR

Answer 7

Structure-Activity Relationships (SAR) - relationship of how structural features of a molecule contribute to or take away from, the desired biological activity

Question 8

HTS

Answer 8

Brute-force approach to determine if a drug target reacts to various chemical compounds

Enabled by integration of robotics, software, liquid handling, sensitive detectors

HTS robots can test 100,000 compounds/day for “hits”

Question 9

3 questions to answer for Target validation:

Answer 9

Accessible to drug delivery (transporters, barriers)?
Required for the physiological process or condition?
Essential (no redundant processes)?

Question 10

What are the theoretical advantages of secondary metabolites over fully synthetic compounds?

Answer 10

• cover a wide range of therapeutic indications
• wide diversity of chemical structures
• chemical properties of 1⁄2 of the small-molecule (

Question 11

Describe the strategic approaches to selection of organisms for drug discovery.

Answer 11

(in order of increasing knowledge base)

Random: no information.

Taxonomic: species driven –> we look for similar species that produce DIFFERENT molecules.

Chemotaxonomic: secondary metabolite driven – > look for species that produces SIMILAR molecules.

Informatics: computational predictiions –> look for SIMILAR molecules molecules in compound library.

Ethnomedical Emperical Evidence: look for ACTIVE MOLECULES from herbal medications.

Question 12

What are other sources of discovery compounds?

Answer 12

• Combinatorial Chemistry
• Rational Drug Design
• in silico Drug Design
• metabolism studies – e.g., fexofenadine (Allegra) vs terfenadine (Seldane)
• historic compound banks

Question 13

What is rational Drug Design?

Answer 13

• Requires greater knowledge about a drug receptor (or other target) or one of its natural ligands to design or identify a lead
• Molecular modeling and QSAR to define physicochemical properties and pharmacophore groups essential for biological activity

Question 14

Describe the basic processes of drug discovery leading to “hits” & leads” and “lead optimization” resulting in “drug candidates”.

Answer 14

Natural & Synthetic products –> Compound Library Bank –> Screening –> Hits (may then alter chemical/functional group modifications to improved PK and PD) –> Leads –> Lead Optimization –> Candidates

Question 15

Define pharmacophore:

Answer 15

The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response

Question 16

Define SAR/QSAR:

Answer 16

The biological activity of molecules is usually measured in assays to establish the level of inhibition of particular signal transduction or metabolic pathways.

Drug discovery often involves the use of QSAR to identify chemical structures that could have good inhibitory effects on specific targets and have low toxicity.

Question 17

Define mechanism of action:

Answer 17

The MOA is the specific biochemical or molecular mechanism by which a drug produces its pharmacological action (pharmacodynamics) and usually includes reference to the specific target.

Question 18

Define biological (or drug or disease) target:

Answer 18

• Enzyme, receptor, transporter, nucleic acid, or other biological molecule
• Part of a key biological process in disease state of interest

Question 19

Define target validation:

Answer 19

• Is the biomolecule:
– Accessible to drug delivery (transporters, barriers)?
– Required for the physiological process or condition?
– Essential (no redundant processes)?