Computational Studies for Development of Triazole‐Pyrimidines as Inhibitor of α‐Tubulin Receptor

Abstract

Abstract Microtubules are among the critical targets for chemotherapeutic agents to fight against cancer because of their crucial role in mitosis. Microtubule inhibitors block cell cycle progression and result in apoptosis, they can frequently disrupt microtubule/tubulin dynamics by binding to the α‐tubulin receptor. To this end, we have developed compounds against α‐tubulin receptor using several tools of computational chemistry: 3D‐QSAR, Molecular Docking, Molecular Dynamics Simulation, and ADMET prediction. The significant findings incorporated two reliable models: CoMFA (Q2=0.75; R 2 =0.89) and CoMSIA (Q 2 =0.57; R 2 =0.78). Molecular Docking was generated and validated using Molecular Dynamics simulation to investigate the binding mode between the most active compound and the α‐tubulin receptor. The results of the MD simulation demonstrated stability over a 100 ns period. Four compounds ( C 1 , C 2 , C 3 , and C 4 ) were developed based on the contour maps, and their activities were predicted. Additionally, Molecular Docking was executed to elucidate the interaction and affinity between the novel compounds and the α‐tubulin receptor. C 1 exhibited high affinity and essential interactions and was subjected to MD simulation studies. The results of the MD simulation revealed that the modifications made to enhance the anticancer activity did not impact stability. Finally, ADMET analysis was utilized to examine drug‐likeness.