Molecular Docking And QSAR Research Of Thrombin And Factor Xa Inhibitors

Thrombosis-related disorders such as deep vein thrombosis, pulmonary embolismand stroke are major cause of morbidity and mortality worldwide. Anticoagulation remains the mainstay of therapy for patients with thrombotic diseases. Although the currently available anticoagulant agents, including heparin, warfarin, and acetylsalicylic acid, have provided remarkable achievements in the treatment of thromboembolic diseases, these drugs have considerable limitations associated with a risk of bleeding and the inconvenience posed by the need for routine coagulation monitoring and/or parenteral administration. The search for small-molecule direct inhibitors of two pivotal enzymes involved in the coagulation cascade,thrombin and factor Xa,have become a focus of novel anticoagulants study.In this paper, molecular docking was employed in the inter-molecule interaction studies on 5 anticoagulant agents systems, namely, phenyl acetamides derivatives, weakly basic azoles derivatives and tetrahydrobenzothiazole derivatives thrombin inhibitors,and pyrrolidine dicarboxylic acid derivatives and benzamidine derivatives FXa inhibitors. Based on the above results, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis(CoMSIA), topomer comparative molecular field analysis(Topomer CoMFA)and hologram quantitative structure activity relationship(HQSAR)were performed to the studies of quantitative structure-activity relationships. The research results are as follows:①The main interactions between phenyl acetamides derivatives and thrombin activity sites are hydrogen bonds, hydrophobic interactions and electrostatic interactions. The optimal model of Topomer CoMFA and HQSAR has a strong predictive ability. The principal components, r~2 and q~2(LOO) of the optimal Topomer CoMFA model are 3, 0.869 and 0.544, respectively. The predictive ability of this model is better than that of the CoMFA and CoMSIA. The best HQSAR model was derived using three fragment distinctions (atom, bond and connections) and fragments size of 5~10. The q~2, r~2 and SEE are 0.604, 0.931 and 0.258, respectively.②There are two different interaction models between weakly basic azoles derivatives and thrombin. The main interactions between this inhibitors and receptor are hydrogen bonds, hydrophobic interactions and van der Waals interactions. The optimal CoMSIA model was established by steric, electrostatic and H-bond donor force fields, The principal components, r~2 and q~2(LOO) are 2, 0.893 and 0.561, respectively. The contribution of each force fields were steric (24%), electrostatic (35.6%) and H-bond donor (40.4%). The contour plot of the model is in agreement with the docking results. The best HQSAR model was derived using four fragment distinctions(bond, connections, hydrogen atom and chirality)and fragments size of 8~10. The q~2, r~2 and SEE are 0.744,0.984 and 0.161, respectively.③The main interactions between tetrahydrobenzothiazole thrombin inhibitors and receptor are hydrogen bonds, hydrophobic interactions and steric effects. The principal components, r~2 and q~2(LOO) of CoMFA are 3, 0.979 and 0.538, respectively. The contributions of force field are steric 65.3% and electrostatic 34.7%. The optimal CoMSIA model was derived using steric, electrostatic and hydrophobic. The principal components, r~2 and q~2(LOO) are 6, 0.990 and 0.566, respectively. The contributions of force field are electrostatic 49.7%, steric 29.3% and hydrophobic 21.0%.④The main interactions between pyrrolidine dicarboxylic acid derivatives and factor Xa are H-bonds, hydrophobic and van der Waals interactions. The Topomer CoMFA model and the optimal HQSAR are of a strong predictive capabilities. The principal components, r~2 and q~2(LOO) of the Topomer CoMFA are 5, 0.946 and 0.605, respectively. Compared to the CoMFA and CoMSIA models based on skeleton alignment, the Topomer CoMFA model is of a stronger predictive capability. The best HQSAR model was derived using 3 fragment distinctions (atom, bond and connections) and fragments size of 6～10. The q~2, r~2 and SEE are 0.527, 0.938 and 0.196, respectively.⑤The main interactions between benzamidine derivatives and factor Xa are hydrogen bonds. Besides, the electrostatic and hydrophobic interactions also play important roles in the interactions between inhibitors and the receptor. The principal components, r~2 and q~2(LOO) of the optimal model of Topomer CoMFA are 2, 0.736 and 0.584, respectively. The SEE is 0.660. The r~2pred of this model is 0.5883. The best HQSAR model was derived using 2 fragment distinctions (atom, Donor and acceptor) and fragments size of 3～8. The q~2, r~2 and SEE are 0.777, 0.996 and 0.071, respectively. The results show that the hydrophobic, H-bond and van der Waals interactions are the primary factors in determining binding affinities of thrombin and Factor Xa inhib itors to thrombin receptor.