Abstract

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were carried out for a series of thienopyrimidines, novel Histamine H1 receptor antagonists. Various models were generated. The best predictive CoMFA model gave significant correlation coefficients (cross-validated r2 (q2) = 0.514, non-cross-validated r2 = 0.925), showing the influence of steric and electrostatic fields. Likewise, the best predictive CoMSIA model gave cross-validated r2 (q2) = 0.541, non-cross-validated r2 = 0.862, eliciting the influence of steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The generated models were externally validated and well correlated with calculated (predicted) and experimental inhibitory concentration (IC50) values, using test sets. The analysis of the contour maps of both CoMFA and CoMSIA models offer important structural insight for designing novel and more active Histamine H1 receptor antagonists prior to their synthesis.

Keywords: CoMFA, CoMSIA, Thienopyrimidine derivatives, 3D QSAR, Histamine, gastric acid, rhinitis, urticaria, fever, asthma