On the modeling of snake venom serine proteinase interactions with benzamidine‐based thrombin inhibitors

Abstract

Pit viper venoms contain a number of serine proteinases that exhibit one or more thrombin‐like activities on fibrinogen and platelets, this being the case for the kinin‐releasing and fibrinogen‐clotting KN‐BJ from the venom of Bothrops jararaca . A three‐dimensional structural model of the KN‐BJ2 serine proteinase was built by homology modeling using the snake venom plasminogen activator TSV‐PA as a major template and porcine kallikrein as additional structural support. A set of intrinsic buried waters was included in the model and its behavior under dynamic conditions was molecular dynamics simulated, revealing a most interesting similarity pattern to kallikrein. The benzamidine‐based thrombin inhibitors α‐NAPAP, 3‐TAPAP, and 4‐TAPAP were docked into the refined model, allowing for a more insightful functional characterization of the enzyme and a better understanding of the reported comparatively low affinity of KN‐BJ2 toward those inhibitors.