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

Abstract

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.

The Fabrication of Docetaxel-Containing Emulsion for Drug Release Kinetics and Lipid Peroxidation

“…It has been proved theoretically that docetaxel has good docking performance with β-tubulin [ 41 ]. Therefore, we also conducted a docking model of β-tubulin with DTX ( Figure 5 A).…”

When Virtual Screening Yields Inactive Drugs: Dealing with False Theoretical Friends

“…A series of representative structures (or clusters) can be subsequently used for conducting VS simulations. MD might be also used to confirm the stability of the binding pose [34,35] . Finally, the simulation of a reduced number of drugs allows to use of more advanced levels of theory, e. g., ab initio or multiscale QM/MM [36,37] .…”

“…MD might be also used to confirm the stability of the binding pose. [34,35] Finally, the simulation of a reduced number of drugs allows to use of more advanced levels of theory, e. g., ab initio or multiscale QM/ MM. [36,37] Such refinements, which are extensive to other viral proteins, [38] pave the way for improving predictions, though all are concomitant with the raise of the computational cost.…”

A switch-on molecular biosensor for detection of caspase-3 and imaging of apoptosis of cells

“…We tested three types of antitumor drugs: 5-fluorouracil (5-FU), which influences the synthesis of nucleic acids (Sara et al, 2018); docetaxel, which obstructs the synthesis of proteins (Sun et al, 2018); and adriamycin, which inhibits the synthesis of RNA and DNA (Blum and Carter, 1974). The concentration of drugs was based on previous reports and considerations of their clinical use.…”