Identify thrombin inhibitor with novel skeleton based on virtual screening study

Virtual screening refers to the screening of active compounds based on a small-molecule database. This procedure can rapidly select active compounds with pharmaceutical properties from millions of molecules, thus considerably reducing the number of experimental screening compounds and cost of drug development and shortening the research cycle. In this paper, a pharmacophore screening method was used for virtual screening to determine new scaffold compounds with potential anticoagulant activities. The pharmacophore model (Model_01-20) was constructed in SYBYL-X 2.0 based on dabigatran derivatives (D1-D9) with micromolar to nanomolar activities and tested by decoy test method. Model_01 was selected to screen more than 1600 million compounds in the Zinc 12.0 database. Furtherly, molecular docking analysis and ADME prediction were conducted on more than 100,000 screened compounds. Finally, two compounds (Z-19 and Z-29) were selected for anticoagulant activity test in vitro, Compound Z-29 with tryptophan aurone structure was found possess anticoagulant effect and its IC50 = 22.9 ± 6.88 μM. ADME prediction results show that compound Z-29 features a high intestinal absorption rate, which is valuable for further in-depth research. The research results of this paper can be used for further structural modification and optimisation to guide the design and provide new ideas and methods for the discovery of new thrombin inhibitors.Communicated by Ramaswamy H. Sarma.