Fighting cancer with microtubule-stabilizing agents: a computational investigation of the complex between β-tubulin and the microtubule-stabilizing, antitumor marine diterpenoid sarcodictyin A

Abstract

The best complex between the marine diterpenoid sarcodictyin A and the protein tubulin is described here from MM-GBSA (molecular mechanics-generalized born surface area) computations of the least effective potential energy of binding. The work started from previous experimental competition experiments, which showed that the sarcodictyins, which are diterpenoids from the stoloniferan coral Sarcodictyon roseum, occupy the same, or overlapping, binding site on tubulin which is taken by paclitaxel (the so-called taxoid binding site). Molecular docking of sarcodictyin A at the taxoid binding site was achieved, with different poses, by using three docking engines and the known coordinates for the experimental complex of non-polymerized α- and β-tubulin with paclitaxel, manually deprived of the latter. These sarcodictyin A-tubulin complexes only served as templates to be subjected, limited to the sarcodictyin A-β-tubulin part, to extensive MD (molecular dynamics) and MM-GBSA simulations with the CHARMM36 force field for the protein and CGenFF force field for the ligand. In contrast, FEP (free energy perturbation) simulations failed to converge with this complex. During MD and MM-GBSA simulations, mutual adaptation of the ligand and receptor was observed. Specifically, stabilization of the complex of lowest effective potential energy of binding, which is submitted here to represent how sarcodictyin A fits into the taxoid binding site of tubulin in nature, resulted from mainly reshaping of the M-loop of β-tubulin, whereby three H-bonds and multiple hydrophobic interactions with sarcodictyin A were established.