3D-QSAR, docking and molecular dynamics for factor Xa inhibitors as anticoagulant agents

Abstract

Factor Xa is an interesting target for design of new anticoagulants as it is positioned at the beginning of the coagulation common pathway. In this study, two different modelling methods, alignment dependent and alignment independent three-dimensional (3D) quantitative structure–activity relationship approaches, including comparative molecular field analysis (CoMFA) and GRid INdependent descriptors (GRIND) (AMANDA), along with molecular docking and molecular dynamics (MD) simulations have been conducted on a series of 50 N1-(5-chloro-2-pyridyl)-2-{[4-(alkylmethyl)benzoyl]amino}-5-chlorobenzamide analogues as factor Xa inhibitors to understand the 3D structural features affecting their inhibitory activity. Validation of the models was done using cross-validation method in addition to the external test set prediction. Both CoMFA (q 2 = 0.66, = 0.97, = 0.56, = 0.55) and GRIND models (q 2 = 0.86, = 0.93, = 0.71, = 0.71) yielded significant statistical results. The sensitivity of the optimised partial least square models was evaluated by performing progressive Y scrambling. In addition, to verify prediction reliability, the chemical applicability domains of the models were checked by the leverage approach. Furthermore, there is a good agreement between CoMFA and GRIND graphical results as well as MD-based docking analysis. The outcomes of this study may result in a better understanding of the inhibition mechanism of factor Xa and aided in the development of new and more potent anticoagulant drugs.