A rational in silico approach to identify inhibitors of Batroxrhagin from Bothrops atrox

Bothrops atrox venom comprises several types of bioactive molecules, enzymatic and non-enzymatic, among those, Batroxrhagin is the most predominant SVMP P-III enzyme, which are responsible for induction of local and systemic hemorrhage and muscle fibers damage, impairing regeneration. Due to great difficulties in establishing an antibothropic drug, new strategies must be addressed to achieve a more effective and efficient treatment. There are no studies of specific catalytic inhibitors of Batroxrhagin. However, there are in vitro studies that have described similar metalloprotease inhibitors. The inhibitor batimastat was used as a leading compound for the search and selection of similar candidates. This molecule is widely cited as a metalloprotease inhibitor and as an antimetastatic. In addition to batimastat-like molecules, four other reported metalloprotease inhibitors were included to compose the study's positive control group. Hence, 580 molecules were tested. The three-dimensional structure of B. atrox Batroxrhagin was predicted based on homologous structures using Modeller 9.20. Molecular docking calculation was performed using Autodock 4.2 and molecular surfaces and interactions were analyzed using Biovia/Discovery Studio 2017. Among 576 molecules, 42 similar to batismast resulted in a better energy of interaction than all positive controls, including batimastat itself. The batimastat-like molecules with lowest energy and positive controls were subjected to molecular dynamics for 30 ns in Gromacs 2019.4. This batimastat-like molecule produced better stability among all the Batroxrhagin-ligand complexes analyzed. Overall, the proposed compounds present justifiable evidence for future in vitro tests aiming to inhibit Batroxrhagin. Communicated by Ramaswamy H. Sarma.