Docking and Molecular Dynamic Simulation in Virtual Screening for computational Design of Novel αβ-Tubulin and Survivin Inhibitors

In the first part of this study, consensus docking of AutoDock and AutoDock Vina has been used for improving the reliability of docking in a virtual screening of a library of 2497 Piperine derivatives, as novel group of Survivin inhibitors. The initial docking of these compounds into the binding site of Survivin, by using AutoDock Vina program, resulted to the selection of top100 derivatives with highest binding affinities. The subsequent screening was done on these 100 compounds by recalculation of binding energies using Auto Dock program. Considering the obtained binding energies, the top two highest ranked compounds, as well as Piperine, were selected and subjected to three independent10 ns molecular dynamics (MD) simulations for further validate the proposed binding modes and interactions. Subsequently, the contributions of van der Waals interactions, electrostatic forces, polar and non-polar solvation in the total binding free energies, accompanying entropy component as a further refinement of total free energy, were calculated using the MMPB/GBSA methods and nabnmode module of AMBER, respectively. In addition to MMBP/GBSA methods, by using alanine scanning, the contribution of each active site residue in to the total binding free energy were assessed. The results represent the main role of hydrophobic forces in molecular interactions and elucidate the binding mode of Piperine analogs for further experimental studies. In this second part of this paper, docking tools were utilized in order to study the binding properties of more than five hundred of proline-based 2, 5-diketopiperazine in the binding site of αβ-tubulin. Results revealed that 20 compounds among them showed lower binding energies in comparison with tryprostatin-A, a well known tubulin inhibitor and therefore could be potential inhibitors of tubulin. However, the precise evaluation of binding poses represents the similar binding modes for all of these compounds and tryprostatin-A. Finally, the best docked complex was subjected to a 25 ns molecular dynamics simulation to further validate the proposed binding mode of this compound.