Computational design of Tryprostatin-A derivatives as novel αβ-tubulin inhibitors

In the first part of this work, binding energies, inhibition constants and binding modes for a group of previously synthesized Tryprostatin-A (TPS-A) derivatives at the binding site of αβ-tubulin have been comprehensively investigated by molecular docking study. The results represent relatively suitable binding energies for these inhibitors in the αβ-tubulin binding site. In the second part, docking tools were utilized in order to design a group of novel analogues of TPS-A. The results of molecular docking reveal that these newly designed molecules have relatively lower binding energies in the pocket of αβ-tubulin. Compound 26 resulted as the best docked molecule with the highest binding affinity (binding energy of -10.74 kcal/mol and calculated inhibition constant of 13.44 nM). In the last part of this study, three representative complexes were subjected to a 25 ns molecular dynamics simulation to further validate the proposed binding modes and interactions. Analysis of the simulation trajectories showed that the root mean square deviation (RMSD) profile of compound 26 was fairly stable during the whole simulation time, indicating that the orientation generated from the docking study is fairly well preserved during the entire length of the simulation. Moreover, the RMSD profiles of compounds 4 and 31 were probably stable in relation to αβ-tubulin after 7 and 14 ns, and these molecular systems were well behaved thereafter. The results of the current study shed some light on the binding mode of TPS-A analogues for further experimental studies.