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RESEARCH ARTICLE
Contents Vol 74(7)

Conformers, Properties of the Anticancer Drug Plocabulin, and its Binding Mechanism with p-Glycoprotein: DFT and MD Studies

Xudong Lü A , Yufei Ma A , Yulian Tao A , Fei Yan A , Ce Song B C , Cuihong Wang https://orcid.org/0000-0002-9443-5237 D and Meiling Zhang https://orcid.org/0000-0002-8241-747X A E
+ Author Affiliations
- Author Affiliations

A School of Biomedical Engineering and Technology, Tianjin Medical University, 22 Qixiangtai Road, Tianjin 300070, China.

B Hefei National Laboratory of Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230026, China.

C Department of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology, SE-10691 Stockholm, Sweden.

D School of Science, Tianjin Chengjian University, 26 Jinjing Road, Tianjin 300384, China.

E Corresponding author. Email: mlzhang@tmu.edu.cn

Australian Journal of Chemistry 74(7) 529-539 https://doi.org/10.1071/CH20320
Submitted: 23 October 2020  Accepted: 29 January 2021   Published: 8 March 2021

Abstract

Plocabulin (PM060184) is a promising new anticancer drug as a microtubule inhibitor. The conformational structure and properties of plocabulin have been studied theoretically. The initial structure was screened by the B3LYP/3-21G* method, and then 32 unique conformations were further optimised with the B3LYP/6-311G* method. The single-point energies were determined at the M06-L/6-311G(2df,p) level. The UV excitation of the most stable plocabulin conformation in methanol was studied by the TD-CAM-B3LYP/6-311G(2df,p) method. High-quality human p-glycoprotein model was obtained through homology modelling. The binding interaction between p-glycoprotein and plocabulin was studied by docking and MD simulation. LEU65, TYR310, ILE340, THR945, PHE983, MET986, and GLN990 were found to be important amino acid residues in the interaction. From a certain perspective, the ‘reverse exclusion’ mechanism of plocabulin with p-glycoprotein was illustrated, and this mechanism provides theoretical guidance for the structural modification of plocabulin and for design of drug’s to avoid p-glycoprotein-mediated drug resistance.


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