P-glycoprotein (P-gp) is responsible for the multidrug resistance (MDR) and involved in the expulsion of xenobiotics out of
cell. In this paper, homology modeling, docking and molecular dynamics simulation (MDS) was performed for the human P-gp
desmosdumotin inhibitor. Docking study was carried out in the P-gp nucleotide binding domain 2 (NBD2). The desmosdumotin binding
region occupied the ATP binding region (flavonoid binding region) with hydrophobic and hydrophilic interactions. Analysis of root mean
square deviations (RMSDs) of active site residues indicated the binding site residues were stable throughout the simulation period. As
shown in previous results with structurally similar flavonoid compounds, van der Waals and electrostatic interactions were found to be
important factors for the desmosdumotin-NBD2 inhibition. Docking results suggest that desmosdumotin interacts with the NBD2 through
both hydrogen bonds (Lys1076, Ser1077 and Thr1078) and hydrophobic interactions (Tyr1044, Val1052, Gly1073 and Cys1074). In
addition, the involvement of other amino-acids was identified via MDS (Lys1076 and Ser1077 for hydrogen bonds and Tyr1044,
Val1052, Gly1073, Cys1074 and Gly1075 for hydrophobic interactions). Thus, current preliminary model of interactions between
desmosdumotin-NBD2 could be helpful to understand the in-depth inhibition mechanism of P-gp at NBD2 level and to design more
potent inhibitors which could effectively overcome MDR of anticancer agents.
Keywords: Anti-cancer agent, desmosdumotin, docking, dynamic simulation, homology modeling, NBD2, P-gp.
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