Week-4: Moore

Question 1

Process of lead optimization

Answer 1

starts with a Primary Assay, then a Design which can be either ligand based or structure based, and then a Chemical Synthesis. After Chemical Synthesis it goes back to Primary Assay.

Question 2

Two Main Objectives of Lead Optimization

Answer 2

increase binding affinity (Ki)

identify more potent derivative (IC50, EC50)

Question 3

Main Goal of Lead Optimization

Answer 3

Is to increase the Therapeutic Index

Question 4

Therapeutic Index

Answer 4

is the ratio of the lethal drug concentration to that which gives therapeutic effects

Question 5

Structure-Activity Relationship SNAR
(DEF.)

Answer 5

DEF. the trend between chemical structure of a compound and its biological activity

It is done by analyzing how small structure changes can impact the biological effect

*SNAR should include a ‘why’ and a ‘how’ component

Question 6

SNAR Structure: Structure

Answer 6

• Functional Groups
• Heterocycles
• Spatial Orientation (stereochemistry, size, and length)

Question 7

SNAR Structure: Activity

Answer 7

• Potency
• Pharmacodynamics
• Solubility
• ADMET

Question 8

Why is SAR Important

Answer 8

allows medicinal chemist to understand how a compound interacts with a biological target

Question 9

3 main reasons SNAR is important

Answer 9

(1) Differentiate portion of molecule required for activity.
(2) Discover portions of the molecule responsible for toxicity and off target effect.
(3) Determine how molecule can be modified to optimize: Potency, Selectivity, and Drug Like Properties.

Question 10

pharmacophore

Answer 10

Is the collection of groups on the molecule that interact with the drug’s receptor (Includes their position and orientation)

Question 11

pharmacophore identification method

Answer 11

is to cut away pieces of the lead and measure the effect of such modification

Question 12

Classic (Total) Synthesis

Answer 12

complete constructions of a complex from readily available starting materials

Question 13

Combinatorial Synthesis

Answer 13

technique used to create large libraries of structurally distinct compounds from a set of “Building Block” molecules A1B1, A2B1, A1B2, A2B2……

Question 14

bioisotere

Answer 14

chemical substitute for a functional group in a drug molecule that has similar biological properties, and chemical and physical similarities

*tautomerization

Question 15

Isosteres

Answer 15

atoms or groups of atoms that have identical or similar outer shell of electrons

carboxylic acid (−COOH) -> sulfonic acid (-SO3H)
amide (-CONH) -> ester (-COO) or thioamide (-CSNH)

Question 16

tautomerization

Answer 16

is a reversible chemical reaction in which a molecule’s structure changes by relocating a hydrogen atom and a double bond to form distinct isomers called tautomers.

Question 17

Lipinski Rule

Answer 17

Molecular weight is > 500
LogP > 5
More than 5 H-bond donors
More than 10 H-bond acceptors

Question 18

Veber Rule

Answer 18

• increased molecular flexibility, as measured by greater than 10 rotatable bonds
• high polar surface area (> 140 A^2)
• total hydrogen bond count (12 donors and acceptors)

Question 19

Drug-likeness

Answer 19

is a concept in drug discovery that describes the likelihood of a chemical compound being a successful drug, considering factors such as (Lipinski’s and Veber Rule)