CADD Studies On FXa Inhibitors And Benzothiazole Derivatives

Coagulation factor Xa (Factor Xa, FXa) is a particularly promising target for novel anticoagulant therapy. The first oral factor Xa inhibitor has been approved in the EU and Canada in 2008. In this paper,38 [6,6,5] Tricyclic Fused Oxazolidinones were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics and Topomer CoMFA(comparative molecular field analysis) were used to build 3D-QSAR models. The results show that the CoMFA model has q2= 0.511 and r2= 0.984, the CoMSIA (comparative molecular similarity indices analysis) model has q2= 0.700 and r2= 0.993 and the Topomer CoMFA analysis has q2= 0.377 and r2= 0.886. The results indicated the steric, hydrophobic, H-acceptor and electrostatic fields play key roles in models. Molecular docking and molecular dynamics explored the binding relationship of the ligand and the receptor protein.Benzothiazole is an important pharmacophore, and it has great applications in drug discovery. Benzothiazole 2-substituted compounds have a certain degree of anti proliferation activity of human hepatocellular carcinoma HepG2 cells. In this work,31 benzothiazole derivatives were studied by three molecular modeling techniques. Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) were used to build 3D-QSAR models. The results show that the CoMFA model has q2= 0.653 and r2= 0.921, and the CoMSIA model has q2= 0.708 and r2= 0.917 and the Topomer CoMFA analysis has q2= 0.386 and r= 0.649. The calculation results are as follows:(1) Ri group favors larger substitution, and R2 group favors small substitution. (2) The potency of the compounds can be increased by addition of hydrophobic groups at the 4-and 6-position of R2. The results obtained from this work suggest that the developed 3D-QSAR model is reasonable for the prediction of the activity of new compounds.