Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
PLoS One. 2012;7(8):e42351. doi: 10.1371/journal.pone.0042351. Epub 2012 Aug 7.
The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several classes of tubulin binding drugs. The molecular basis of drug resistance of the tubulin mutants is yet to be unraveled. Here, we employ molecular dynamics simulations, protein-ligand docking, and MMPB(GB)SA analyses to examine the binding of anticancer drugs, taxol and epothilone to the reported point mutants of tubulin--T274I, R282Q, and Q292E. Results suggest that the mutations significantly alter the tubulin structure and dynamics, thereby weaken the interactions and binding of the drugs, primarily by modifying the M loop conformation and enlarging the pocket volume. Interestingly, these mutations also affect the tubulin distal sites that are associated with microtubule building processes.
微管二聚体在细胞分裂中的重要作用使其成为一个有吸引力的药物靶点。靶向微管的药物在治疗各种癌症方面取得了显著的临床成功。然而，这些药物的疗效因微管突变体的出现而减弱，这些突变体对几类微管结合药物不敏感。微管突变体的耐药性的分子基础尚未被揭示。在这里，我们采用分子动力学模拟、蛋白-配体对接和 MMPB(GB)SA 分析来研究报道的微管点突变体——T274I、R282Q 和 Q292E 与抗癌药物紫杉醇和埃坡霉素的结合。结果表明，这些突变显著改变了微管的结构和动力学，从而削弱了药物的相互作用和结合，主要是通过改变 M 环构象和扩大口袋体积。有趣的是，这些突变还影响与微管构建过程相关的微管远端部位。
