Modification of the tubulin-microtubule (Tub-Mts) system has generated effective strategies for developing different treatments for cancer. A huge amount of clinical data about inhibitors of the tubulin-microtubule system have supported and validated the studies on this pharmacological target. However, many tubulin-microtubule inhibitors have been developed from representative and common scaffolds that cover a small region of the chemical space with limited structural innovation. The main goal of this study is to develop the first consensus virtual screening protocol for natural products (ligand- and structure-based drug design methods) tuned for the identification of new potential inhibitors of the Tub-Mts system. A combined strategy that involves molecular similarity, molecular docking, pharmacophore modeling, and in silico ADMET prediction has been employed to prioritize the selections of potential inhibitors of the Tub-Mts system. Five compounds were selected and further studied using molecular dynamics and binding energy predictions to characterize their possible binding mechanisms. Their structures correspond to 5-[2-(4-hydroxy-3-methoxyphenyl) ethyl]-2,3-dimethoxyphenol (1), 9,10-dihydro-3,4-dimethoxy-2,7-phenanthrenediol (2), 2-(3,4-dimethoxyphenyl)-5,7-dihydroxy-6-methoxy-4H-1-benzopyran-4-one (3), 13,14-epoxyparvifoline-4',5',6'-trimethoxybenzoate (4), and phenylmethyl 6-hydroxy-2,3-dimethoxybenzoate (5). Compounds 1-3 have been associated with literature reports that confirm their activity against several cancer cell lines, thus supporting the utility of this protocol.
Keywords: ADMET; Anti-cancer; Cell-based assays; Drug discovery.
© 2022 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.