Quercetin acts as a P-gp modulator via impeding signal transduction from nucleotide-binding domain to transmembrane domain

Abstract

The inherent ability of the cancer cells to resist chemotherapeutic agents is a major challenge in drug discovery. Chemotherapy is one of the most widely used treatment methods for cancer, but due to multidrug resistance (MDR) development in cancer cells, the healing procedure often fails. Various factors impart cancer resistance to cells; among them, P-glycoprotein (P-gp) overexpression is directly linked to MDR in cancer cells. P-gp leads to the efflux of drug molecules to the extracellular space. Several molecules have been reported to inhibit the P-gp activity. Among them, quercetin has revealed a great potential to modulate P-gp activity. However, the mechanistic understanding of quercetin induced modulation is not entirely elucidated. In the present work, we showed that quercetin binds in the interacting region between the transmembrane domain and nucleotide-binding domain out of the three plausible binding sites of P-gp and restrict the conformational change from inward- to outward-facing conformation of P-gp. Due to the absence of the inward-facing structure of human P-gp, we first modeled an inward-facing P-gp structure. Using molecular docking, the interacting residues of P-gp were identified, and the stability and interaction dynamics of the complex were studied using molecular dynamics simulation. Our work reveals the mechanistic understanding of quercetin induced modulation of P-gp and indicates its importance in cancer treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cancer
• multidrug resistance
• P-glycoprotein
• quercetin
• intracellular helices

Acknowledgment

The authors gratefully acknowledge the BioX Centre of the Indian Institute of Technology Mandi for providing all the necessary facilities for the completion of this work. A.S. acknowledges University Grants Commission, India for Doctoral research fellowship. N.G. acknowledges the Science and Engineering Research Board grant, India (ECR/2017/000926) for financial support.

Authors’ contributions

Conceptualization: A.S., N.G.; methodology and analysis: A.S., S.K.P., P.K., K.C.D.; writing and original draft preparation: A.S., S.K.P., N.G.; review and editing: A.S., D.V., R.S., T.T., R.G., N.M.; supervision: N.G. All authors have read and agreed to the submitted version of the manuscript.

Disclosure statement

The authors declare no conflict of interest.