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2. DRUG DESIGN & RELATION OF FUNCTIONAL GROUPS.pptx
1.
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
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°