Three-Dimensional Quantitative Structure−Activity Relationships and Activity Predictions of Human TRPV1 Channel Antagonists:  Comparative Molecular Field Analysis and Comparative Molecular Similarity Index Analysis of Cinnamides

• Published in: Journal of medicinal chemistry 2007-11, Vol.50 (23), p.5608-5619
• Main Authors: Viswanadhan, Vellarkad N, Sun, Yaxiong, Norman, Mark H
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Animals; Biological and medical sciences; Cinnamates - chemistry; Humans; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Rats; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070261k

3D-QSAR models for human TRPV1 channel antagonists were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), using a training set of 61 cinnamide TRPV1 antagonists and tested on an independent test set of 47 antagonists. Molecular alignment procedure included weights for both internal energy and atom-to-atom matching against a reference or probe. Sensitivity of results on partial charge assignments was explored using multiple charge sets. AM1-BCC charge assignments gave better results for both CoMFA and CoMSIA models. For the best CoMFA model, the statistics are, r 2 = 0.96, q 2 = 0.58, n = 61 for the training set and r 2 = 0.50, n = 47 for the test set. For the best CoMSIA model, the statistics are r 2 = 0.95, q 2 = 0.57, n = 61 for the training set and r 2 = 0.48, n = 47 for the test set. These models are consistent with the proposed binding modes and interactions of known activators of the TRPV1 channel such as capsaicin, in a structural model of the TM3/4 helical region of TRPV1.