Chemical Properties: Hydrogen bonding capabilities.
Examples: Thousands of descriptors can be calculated for analysis.
Electronic Descriptors
Hammett Equation: Utilizes dissociation constants of substituted benzoic acids.
Dissociation Constant (K): Varies based on substituent position (ortho, meta, para) and type.
Electron-Withdrawing vs. Electron-Donating Groups:
Electron-withdrawing groups stabilize the anion form (high K).
Electron-donating groups stabilize the acid form (low K).
Importance of Electron Effects
Antibacterial Activity: Sulfa drugs mimic para-aminobenzoic acid (substrate for bacteria).
The active form is the anion, not the neutral form.
Activity influenced by substituent types (donating vs. withdrawing).
Acyclic and Hydrolysis Effects
Hydrolysis of Esters: Affected by nucleophilic attack on carbonyl carbon.
Effect of R Group Size: Larger R groups hinder nucleophilic attack, decreasing activity (Taft parameter).
Overall Activity Trends: Small R increases activity; larger R decreases it.
Log P (Partition Coefficient)
Definition: Log P = log ([octanol]/[water])
Indicates hydrophilicity/hydrophobicity.
Higher Log P = more hydrophobic; lower Log P = more hydrophilic.
Applications: Correlated with drug absorption, distribution, and activity.
Log P and Drug Activity
Anticonvulsant Activity: Relates to Log P; more hydrophobic compounds show increased activity.
Anesthetic Activity: Follows a parabolic relationship with Log P, indicating an optimal value around 2.3 for maximum activity.
Hammett and Taft Parameters
Hammett Substituent Constant (Sigma): Measures electron-withdrawing or donating influence.
Taft Steric Parameters: Measures steric effects in aliphatic systems (no resonance).
Calculation: Based on rates of hydrolysis under different conditions.
Comparative Analysis of Substituents
Crane Plot: Used for evaluating substituents based on hydrophobicity (pi) and electronic effects (sigma).
Orthogonality: Important for selecting substituents; ensures varied activity without correlation.
Toppan Scheme for QSAR Analysis
A systematic approach for synthesizing new molecules to maintain a balance of hydrophobic and electronic properties.
Selection Criteria: Substituents should provide a range of values for properties studied, ensuring orthogonality.
Conclusion
QSAR is a vital tool for drug design and development, leveraging statistical relationships to predict biological activity based on molecular structure.