Chapter 2: Drug Design and Relationship of Functional Groups to Pharmacologic Activity
Introduction

Relationship Between Molecular Structure and Biologic Activity

Crum-Brown and Fraser - did studies on this relationship in 1869. Their initial hypothesis that one functional group = one biologic action was incorrect, but they demonstrated the concept that molecular structure influenced biologic activity.

Selectivity of Drug Action and Drug Receptors

When the action of acetylcholine was discovered, it was known that one chemical group could produce two different biologic effects.
Antagonists are molecules that block the effects of natural neurotransmitters (norepinephrine, histamine, dopamine, seratonin) and are usually larger in size than the native compound. Antagonists to peptide neurotransmitters and hormones (cholecystokinin, melanocortin) are usually smaller in size.
Both agonists and antagonists share structural components with the native compound and the neurotransmitter that they influence.
SARs: structure-activity relationships (underlying principle for medicinal chemistry)
Different functional groups can yield chemical entities with similar physiochemical properties (i.e. sulfanilamide antibiotics - sulfanilamide acts as an antagonist to PABA metabolism in bacteria because they share similar steric and electronic properties)

Biologic Targets for Drug Action

Physiochemical Properties of Drug
Acid-Base Properties of Drugs
Relative Acid Strength (pKa)
Predicting the Degree of Ionization of a Molecule
Water Solubility of Drugs
Hydrogen Bonds
Ionization
Predicting Water Solubility: The Empirical Approach
Predicting Water Solubility: Analytical/Quantitative Approach

Stereochemistry and Drug Action
Stereochemical Definitions
Disignation of Absolute Configuration
Stereochemistry and Biologic Activity
Easson-Stedman Hypothesis
Diastereomers
Conformational Isomerism

Drug Design: Discovery and Structural Modification of Lead Compounds
Process of Drug Discovery
Natural Product Screening
Drug Discovery via Random Screening of Synthetic Organic Compounds
Drug Discovery from Targeted Dedicated Screening and Rational Drug Design
Drug Discovery via Drug Metabolism Studies
Drug Discovery from the Observation of Side Effects
Refinement of the Lead Structure
Determination of the Pharmacophore
Alterations in Alkyl Chains: Chain Length, Branching, and Rings
Functional Group Modification: Bioisosterism
Bioisosterism
Classical and Nonclassical Bioisosteres
Classical
Nonclassical

Peptide and Protein Drugs
Physical and Chemical Properties of Peptides
Metabolism/Degradation of Peptide and Protein Drugs

Summary

	Created by Shannon Grady over 11 years ago

Medicinal Chemistry (CH2) Note on Outline Chapter 2, created by Shannon Grady on 10/08/2013.