Exploration of anti-tumour inhibitors from colchicine derivatives based on 3D-QSAR, molecular docking and molecular dynamics simulations

• Published in: Molecular simulation 2023-11, Vol.49 (17), p.1647-1665
• Main Authors: Tong, Jian-Bo, Liu, Yuan, Xiao, Xue-chun, Gao, Peng, Xu, Hai-yin
• Format: Article
• Language: English
• Subjects: Amino acids; Anticancer properties; Binding; Bonding strength; Chemical bonds; Colchicine; Hydrogen bonds; Inhibitors; Microtubule protein inhibitor; Molecular docking; Molecular dynamics; Proteins; Screening; Simulation; Topomer coMFA
• ISSN: 0892-7022; 1029-0435
• DOI: 10.1080/08927022.2023.2259499

Microtubulin is an important research target for anti-tumour drugs, which can be used to inhibit microtubulin polymerisation and improve the efficacy of tumour therapy. In this paper, 61 microtubule protein inhibitors with anticancer activity are selected as the data set for building a stable and effective QSAR (Topomer CoMFA) model, resulting in a Topomer CoMFA model with validation coefficients of  = 0.737 and   = 0.922. Fifteen new inhibitors with theoretically high activity are designed by screening the zinc database for new fragments with good activity through the contribution descriptors obtained by Topomer CoMFA. After simulating the binding affinity and interaction of the inhibitors with the proteins by molecular docking, all these compounds formed strong interactions such as hydrogen bonds with multiple amino acids in the receptor proteins. Furthermore, molecular dynamics results show that the predicted highly active compounds exhibited stable and favourable binding patterns to the active pocket. In addition, these new compounds exhibit good ADMET properties. The present work establishes a reliable QSAR model for computational simulation screening of microtubulin drug development and provides a basis for further access to novel microtubulin inhibitors.