Pharmacophore Model Generation of Thrombin Inhibitors

Xing Wang, Yanling Zhang, Yuhong Xiang, Zhenzhen Ren, Yanjiang Qiao

Department of Chemistry, Capital Normal University, Beijing 100048, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China.

DOI: 10.4236/jsea.2012.512B017                

Abstract

Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors.  Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.

Keywords

Cardiovascular disease; thrombin; Pharmacophore; Virtual screening

Conflicts of Interest

The authors declare no conflicts of interest.

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