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.
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, r2 = 0.96, q2 = 0.58, n = 61 for the training set and r2 = 0.50, n = 47 for the test set. For the best CoMSIA model, the statistics are r2 = 0.95, q2 = 0.57, n = 61 for the training set and r2 = 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.
Viswanadhan
Vellarkad N
VN
Molecular Structure and Design, Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1789, USA. visv@amgen.com
Sun
Yaxiong
Y
Norman
Mark H
MH
D000577:Amides / Q000737:chemistry*; D000818:Animals; D002934:Cinnamates / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000577:Amides; D002934:Cinnamates; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C029010:cinnamic acid