Discovery of microtubule stabilizers with novel scaffold structures based on virtual screening, biological evaluation, and molecular dynamics simulation

• Published in: Chemico-biological interactions 2022-01, Vol.352, p.109784-109784, Article 109784
• Main Authors: Mao, Jun, Luo, Qing-Qing, Zhang, Hong-Rui, Zheng, Xiu-He, Shen, Chen, Qi, Hua-Zhao, Hu, Mei-Ling, Zhang, Hui
• Format: Article
• Language: English
• Subjects: A549 Cells; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Cell Proliferation - drug effects; Databases, Chemical; Drug Discovery; Drug Screening Assays, Antitumor - methods; HeLa Cells; Hep G2 Cells; Humans; Interacting fingerprint; MCF-7 Cells; Microtubules - drug effects; Microtubules - metabolism; Molecular docking; Molecular Docking Simulation; Molecular dynamic; Molecular Dynamics Simulation; Molecular Structure; Structure-Activity Relationship; Tubulin; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; User-Computer Interface; Virtual screening
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2021.109784

Disrupting the dynamics and structures of microtubules can perturb mitotic spindle formation, cause cell cycle arrest in G2/M phase, and subsequently lead to cellular death via apoptosis. In this investigation, the structure-based virtual screening methods, including molecular docking and rescoring, and similarity analysis of interaction molecular fingerprints, were developed to discover novel tubulin inhibitors from ChemDiv database with 1,601,806 compounds. The screened compounds were further filtered by PAINS, ADME/T, Toxscore, SAscore, and Drug-likeness analysis. Finally, 17 hit compounds were selected, and then submitted to the biologic evaluation. Among these hits, the P2 exhibited the strongest antiproliferative activity against four tumor cells including HeLa, HepG2, MCF-7, and A549. The in vitro tubulin polymerization assay revealed P2 could promote tubulin polymerization in a dose dependent manner. Finally, in order to analyze the interaction modes of complexes, the molecular dynamics simulation was performed to investigate the interactions between P2 and tubulin. The molecular dynamics simulation analysis showed that P2 could stably bind to taxane site, induced H6–H7, B9–B10, and M-loop regions changes. The ΔGbind energies of tubulin-P2 and tubulin-paclitaxel were −68.25 ± 12.98 and −146.05 ± 16.17 kJ mol−1, respectively, which were in line with the results of the experimental test. Therefore, P2 has been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity. [Display omitted] •Microtubule was considered as an attractive drug target for anticancer therapy.•The multilayer virtual screening methods were used to discover novel tubulin inhibitor.•P2 displayed the strongest anti-proliferative activity against HeLa, A549, MCF-7 and HepG2 cancer cells.•P2 could effectively promote in vitro tubulin polymerization.•The molecular dynamics simulation was performed to investigate the interactions between P2 and tubulin.