Additivity of Molecular Fields:  CoMFA Study on Dual Activators of PPARα and PPARγ

• Published in: Journal of medicinal chemistry Vol. 48; no. 8; pp. 3015 - 3025
• Main Authors: Khanna, Smriti, Sobhia, M. E, Bharatam, Prasad V
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 21.04.2005
• Subjects: Biological and medical sciences; General and cellular metabolism. Vitamins; Medical sciences; Pharmacology. Drug treatments; Agonist; Ether; Benzene derivatives; Prediction; Thiazolidinedione derivatives; Cycloalkane; PPAR-γ receptor; Modeling; PPAR-α receptor; Three dimensional model; Structure activity relation; Molecular model; Comparative molecular field analysis method; Affinity; Electrostatic model
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049383s

Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce the concept of additivity of molecular fields to correlate molecular fields of dual activators and their pIC50 values. PPARα and PPARγ dual activators, which affect hypertriglyceridemia and hyperglycemia, have been chosen to validate the molecular field additivity concept. Three CoMFA models namely α-model, γ-model and dual-model have been developed. The validity of this concept has been ascertained by (a) comparing contour maps, (b) by comparing CoMFA results with FlexX docking results and (c) by analyzing newly designed molecules.