Pharmacogenomics of drug resistance in Breast Cancer Resistance Protein (BCRP) and its mutated variants

Abstract

Aim

Drugs in breast cancer treatment suffer resistance and drug efflux from ATP-binding cassette (ABC) efflux transporter protein. Drugs inhibiting BCRP suffer activity alteration due to sequence variants. It is imperative to investigate role of mutant variants using structure based aspects of drug binding.

Method

In present work, we included single nucleotide polymorphisms like F208S, S248P and F431L in BCRP structure and evaluated their role in alteration of drug binding affinities using computational approaches. Comparative modeling of BCRP 3D structure was achieved using various tools available followed by structure validation. Mutagenesis and its impact by SNPs was attained in 3D structure of BCRP. A set of selected and established BCRP inhibitors were further docked into binding site to record the drug resistance in mutant variants.

Results

Nucleotide binding (NB) domain (258 AA) and transmembrane (TM) domain (291 AA) of BCRP were modeled separately and assembled together to generate a single structure. Ramachandran Plot confirmed quality of modeled structures along with main chain and side chain parameters. Mutagenesis included three main variants (F208S, S248P and F431L) using Triton program. Molecular docking results showed inhibitor CID_25223199 binding effectively to wild and F431L mutant structure of BCRP while inhibitors CID_25223002 to F208S and CID_119373 to S248P.

Conclusion

Distortion in spatial arrangement of amino acids in BCRP protein due to mutations led to low efficacy in drug response with respect to wild isoform. Results of present work demand to probe pharmacogenomic aspects in drug development efforts for breast cancer.