Abstract
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.
Highlights
Microtubules (MT) are dynamic cytoskeletal polymers made up of ab-tubulin heterodimers
Crystallographic studies, have shown that the binding motifs of these two drugs are quite different and unique [13,14]. Both taxol and epothilone still continue to serve as the lead compounds for the development of new antimitotic drugs. These anti-mitotic drugs have been successful in treating various cancers, their efficacy is severely limited by the emergence of tubulin mutants, which are unsusceptible to several classes of tubulin inhibitors
We investigated the structural features of wild type ab-tubulin dimer and its three drug resistant variants through all-atom MD simulations
Summary
Microtubules (MT) are dynamic cytoskeletal polymers made up of ab-tubulin heterodimers. Taxanes are widely used in the treatment of lung, breast, ovarian, prostrate cancers and AIDS related Kaposi’s sarcoma [7] Epothilones are another class of microtubule stabilizing drugs, used in the treatment of advanced breast cancer and in a subset of paclitaxel refractory tumors [8]. These 16 membered macrolides are structurally dissimilar to taxol, they show microtubule stabilizing mechanism similar to taxol [9]. Crystallographic studies, have shown that the binding motifs of these two drugs are quite different and unique [13,14] Both taxol and epothilone still continue to serve as the lead compounds for the development of new antimitotic drugs. These anti-mitotic drugs have been successful in treating various cancers, their efficacy is severely limited by the emergence of tubulin mutants, which are unsusceptible to several classes of tubulin inhibitors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
