Conformers, properties, and docking mechanism of the anticancer drug docetaxel: DFT and molecular dynamics studies.

The conformational structures and properties of the anticancer drug docetaxel (DTX) are studied theoretically. A total of 3888 trial structures were initially generated by all combinations of internal single-bond rotamers and screened with the B3LYP/3-21G* method. A total of 31 unique conformers were further optimized at the B3LYP/6-311G* method. Their relative energies, dipole moments, rotational constants, and harmonic vibrational frequencies were predicted. Single-point relative energies were then determined at the M06-L/6-311G(2df,p) level. The UV spectrum of the lowest-lying DTX conformer in methanol was investigated with the TD-CAM-B3LYP/6-311 + G(2df,p) method. The 31 unique DTX structures are mainly docked at three different sites within β-tubulin. Based on the results of molecular docking and double-float MD simulations, the lowest-lying DTX conformer consistently exhibits good docking performance with β-tubulin. We identified the residues LYS299, ARG215, GLN294, LEU275, THR216, GLU290, PRO274, and THR276 on β-tubulin as active sites forming a binding pocket responsible for locking DTX within β-tubulin to make the combination more stable. The RMSD values show that the predicted complexes are favorable, and the SASA analysis shows that the hydrophilic properties of DTX are better than paclitaxel. © 2018 Wiley Periodicals, Inc.