The document discusses the relationship between a drug's molecular structure and its biological activity. It covers key topics like how functional groups contribute to a drug's pharmacological effects, the role of receptors in drug selectivity and action, and how physicochemical properties like acidity and stereochemistry impact solubility, binding to targets, and a drug's overall activity. It provides examples to illustrate these structure-activity principles, which were established through seminal findings like Crum-Brown and Fraser's work with quaternary ammonium compounds and the discovery of acetylcholine by Loewi and Navrati.

2. Drug Design and
Relationship of Functional
Groups to Pharmacologic
Activity
Presented to : Prof. Dr. Rao Saeed Sahb
Presented by : Aamna Khatoon
Mphil pharmaceutical Chemistry , 1st Semester
Drug Design and Drug Development

3. Introduction
Relationship between Molecular Structure and Biological
Activity
Selectivity of Drug action and Receptors
1. Biologic targets for drug action
Physicochemical Properties of Drugs
1. Acid-Base Properties
2. pKa (Relative acid strength)
3. Degree of ionization
4. Water solubility
5. Hydrogen bonding
Stereochemistry and Drug action
1. Designation of absolute configuration
2. Stereochemistry and biologic activity
3. Diastereomers
4. Conformational isomerism

4. RELATIONSHIP BETWEEN MOLECULAR
STRUCTURE AND BIOLOGICAL
ACTIVITY
Crum-Brown and Fraser- 1869
Quaternary Ammonium compounds
Opened new era for research
Postulate- one chemical group gives one biological action
Discovery of Acetylcholine- Loewi & Navrati

5. SELECTION OF DRUG ACTION AND
DRUG RECEPTORS
Background
Ehrlich postulate : complementary Side Chains – Cell surface , magic bullet
Arsenicals – thiol group (-SH)- toxic to trypanosomes
Albert –Selective toxicity
Ing hypothesis : Acetylecholine paradox
 one functional group – different effect
same receptor –size of molecule –more complementary manner

6. Biological Targets for Drug Action
Interaction with biological target – Pharmacological activity
Targets : receptor , enzyme ,nucleic acid or excitable membrane
Woods demonstration : (1940), PABA and Sulfanilamide
(Sulphonamide)
Drug : Functional group , physicochemical properties, 3D “fit”
Pharmacokinetics of drug

7. PHYSICOCHEMICAL PROPERTIES OF
DRUGS

8. Acid-Base Properties
Human body -70-75%
Most Appropriate concept – Bronsted-Lowry Theory

9. Relative Acid Strength (pKa)
Negative log of acid dissociation constant or Ka value
Lower pKa means an acid is completely dissociated in water
Amphoteric nature of Water – Leveling effect
Most of the drugs are weak acids or weak bases
 Predicting the Degree of Ionization of a Molecule
Relationship of pKa and pH
Henderson Hesselbalch equation

10. Degree of Ionization
Hydrogen bonding
Type of interaction
Ion dipole interaction
Relation with pKa and pH
Zwitter ion

11. Predicting Water Solubility
The empirical Approach
Lemke development
Solubilizing potential of functional group
Total number of carbons in a compound
If Solubilizing potential is > total number of carbons = soluble in water
If Solubilizing potential is < total number of carbons = insoluble in water
Example : Anileridine = no.of carbons 21, solubilizing potential =9 carbons
Anileridine hydrochloride = solubilizing potential = 29-39 carbons

12. Predicting Water Solubility
Analytical and Quantitative Approach
Based on Partition Coefficient
 π value of hydrophobic substituents –assigned to each functional group
Clog P value > +0.5 then compound is water insoluble
Clog P value < +0.5 then compound is water soluble
Example : Anileridine

13. Stereochemistry and Drug Action
Stereoisomers : Molecules having same number and kind of atoms
but different three dimensional structure
Enantiomers : Mirror images , non superimposable, chiral center,
optical rotation
Diastereisomers : all other isomers other than enantiomers
• Geometric isomers , have different physiochemical properties
• Spatial arrangements – asymmetrical environment
• Pharmacokinetics and Pharmacodynamics properties

14. Designation of Absolute Configuration
Optical Rotation : at 1st enantiomers were distinguished
• +/D – clockwise rotation/ right side of plane polarized light
• Limitation : physical property does not explain 3D structure
Fisher and Rosanoff : 19th century , nomenclature based on
glyceraldehyde
• Worked for simple molecules – determined based on chemical
degradation , and synthetic methods .
• Became cumbersome for compounds having more than one chiral
centers.

15. Designation of Absolute Configuration
Sequence Rule or CIP system
Introduced by Cohn in 1956
Chiral Centre is ranked based on priority given to atom with highest
atomic number – extends to next item until a priority is established .
Example glucose , norepinephrine
Priority sequence toward right – named as R isomer
Priority sequence toward left – Named as S isomer
Example : norepinephrine and propranolol.

16. Stereochemistry and Biological Activity
1886 – Piutti – physiological Action of Asparagine
1933- Easson and Stedman explained reason for difference in
biological activity of enantiomers
• Correct spatial orientation is required for maximum interaction with
receptor sites
• Example R-(-) epinephrine , L –(+)epinephrine , N methyldopa
• Spatial orientation also impact on ability of a molecule to reach the
target receptor
Enantioselective biological environment – significant difference in
pharmacological activity of one enantiomer

17. Diastereomers
Non superimposable
Non mirror images
More than one chiral centers
• Different physiochemical and biological activity
• Example Ephedrine and psuedoephidrine
Restricted double bond rotation
• Z(zusammen) and E (entgegen)forms
• 1968 – Blackwood nomenclature (like cohn)
• High priority substituents on same side of double bond = Z(cis)
• High priority substituents on opposite side of double bond = E(trans)
• Geometric isomers of triprolidine (H1- receptor antagonist)

18. Conformational isomerism
Stereoisomers resulted from the rotation about one or more single
bonds .
Non-identical spatial arrangement of atoms
Much energy is not required – such conversions can occur at room
temperature
Example :
 Acetylecholine – stereoisomers 60°, 120°,180°,240°
Most stable 120°

20. THANK YOU