Complete reconstruction of the unbinding pathway of an anticancer drug by conventional unbiased molecular dynamics simulation

Abstract

11Understanding the details of unbinding mechanism of small molecule drugs is an 12 inseparable part of rational drug design. Reconstruction of the unbinding pathway of small 13 molecule drugs, todays, can be achieved through molecular dynamics simulations. Nonetheless, 14 simulating a process in which a drug unbinds from its receptor demands lots of time, mostly up 15 to several milliseconds. This amount of time is neither reasonable nor affordable; therefore, 16 many researchers utilize various biases that there are still many doubts about their 17 trustworthiness. In this work we have utilized short-run simulations, replicas, to make such time-18 consuming process cost effective. By replicating those snapshots of the trajectories which, after 19 careful analyses, were selected as potential candidates we increased our system's efficiency 20 considerably. As a matter of fact, we have implemented a sort of human bias, inspecting 21 trajectories visually, to achieve multiple unbinding events. We would like to call this stratagem, 22 replicating of potent snapshots, "rational sampling" as it is, in fact, benefiting from human logic. 23In our case, an anticancer drug, the dasatinib, completely unbounded from its target protein, c-24 Src kinase, in only 392.6 ns, and this was gained without applying any internal biases and 25 potentials which can increase error level. Thus, we achieved important structural details that can 26 alter our viewpoint as well as assist drug designers. 27 2