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.