In silico analysis of a few dietary phytochemicals as potential tumor chemo-sensitizers

Abstract

P-glycoprotein (P-gp) is a membrane ATP-binding cassette (ABC) transporter that extrudes different xenobiotics out of cells. Besides its tissue protection role, overexpression of P-gp on the surface of many neoplastic cells restricts the cell entry of many anti-cancer drugs, the phenomenon which is known as multidrug resistance (MDR). It has been demonstrated that MDR cells can be sensitized toward anti-cancer agents when treated with P-gp inhibitors/modulators known as chemo-sensitizers. Due to the clinical significance and also considering the fact that many P-gp inhibitors are transported by P-gp, the search for more potent and low toxic non-transported chemo-sensitizers is an active area of research. Regarding this, several naturally occurring compounds were reported as MDR reversal agents, a category which is generally referred to as “fourth-generation P-gp inhibitors.” Dietary supplements containing natural products are widely used, and it is possible that they interact with co-administered pharmaceutical substances that are P-gp substrates, leading to altered pharmacokinetic profile. In silico approaches for quantitative and quantitative prediction of binding mechanism of dietary natural products to P-gp may be regarded as appropriate strategy in the early phase of drug discovery projects since they describe structural features of various phytochemicals for interaction with P-gp and pave the way toward alternative and novel anti-MDR scaffolds. In the present contribution, some phytochemicals of turmeric, black pepper, and green tea as commonly consumed dietary sources were subjected to systematic combined in silico analysis including molecular docking and amino acid decomposition analysis through B3LYP functional in association with 6-31G basis set. On the basis of major identified drug binding sites within P-gp internal pocket, modeled natural compounds were categorized as substrate, inhibitor, or modulator while structure binding relationship of each category was developed and elucidated.