Virtual screening of ABCC1 transporter nucleotidebinding domains as a therapeutic target in multidrug resistant cancer.

Kanin Rungsardthong,Jeffrey Penny,Sergio Mares-Sámano

doi:10.6026/97320630008907

Abstract

ABCC1 is a member of the ATP-binding Cassette super family of transporters, actively effluxes xenobiotics from cells. Clinically, ABCC1 expression is linked to cancer multidrug resistance. Substrate efflux is energised by ATP binding and hydrolysis at the nucleotide-binding domains (NBDs) and inhibition of these events may help combat drug resistance. The aim of this study is to identify potential inhibitors of ABCC1 through virtual screening of National Cancer Institute (NCI) compounds. A threedimensional model of ABCC1 NBD2 was generated using MODELLER whilst the X-ray crystal structure of ABCC1 NBD1 was retrieved from the Protein Data Bank. A pharmacophore hypothesis was generated based on flavonoids known to bind at the NBDs using PHASE, and used to screen the NCI database. GLIDE was employed in molecular docking studies for all hit compounds identified by pharmacophore screening. The best potential inhibitors were identified as compounds possessing predicted binding affinities greater than ATP. Approximately 5% (13/265) of the hit compounds possessed lower docking scores than ATP in ABCC1 NBD1 (NSC93033, NSC662377, NSC319661, NSC333748, NSC683893, NSC226639, NSC94231, NSC55979, NSC169121, NSC166574, NSC73380, NSC127738, NSC115534), whereas approximately 7% (7/104) of docked NCI compounds were predicted to possess lower docking scores than ATP in ABCC1 NBD2 (NSC91789, NSC529483, NSC211168, NSC318214, NSC116519, NSC372332, NSC526974). Analyses of docking orientations revealed P-loop residues of each NBD and the aromatic amino acids Trp653 (NBD1) and Tyr1302 (NBD2) were key in interacting with high-affinity compounds. On the basis of docked orientation and docking score the compounds identified may be potential inhibitors of ABCC1 and require further pharmacological analysis.AbbreviationsABC - ATP-binding cassette, DHS - dehydrosilybin, MDR - multidrug resistance, NBD - nucleotide-binding domain, PDB - protein data bank.

Highlights

ABCC1 is a member of the ATP-binding Cassette super family of transporters, actively effluxes xenobiotics from cells
Since ATP binding and hydrolysis are fundamentally important to active drug efflux, targeting agents to the nucleotide-binding domains (NBDs) to disrupt the catalytic cycle is a potential strategy for addressing ABCC1-mediated cancer multidrug resistance
In this study, flavonoids and flavonoid-based compounds were used as input ligands for pharmacophore generation to identify potential modulators of ABCC1 NBDs using both ligand- and structure-based approaches

Summary

Introduction

ABCC1 is a member of the ATP-binding Cassette super family of transporters, actively effluxes xenobiotics from cells. Substrate efflux is energised by ATP binding and hydrolysis at the nucleotide-binding domains (NBDs) and inhibition of these events may help combat drug resistance. The aim of this study is to identify potential inhibitors of ABCC1 through virtual screening of National Cancer Institute (NCI) compounds. Abbreviation: ABC: ATP-binding cassette, DHS: dehydrosilybin, MDR: multidrug resistance, NBD: nucleotide-binding domain, PDB: protein data bank. Since ATP binding and hydrolysis are fundamentally important to active drug efflux, targeting agents to the NBDs to disrupt the catalytic cycle is a potential strategy for addressing ABCC1-mediated cancer multidrug resistance. In this study, flavonoids and flavonoid-based compounds were used as input ligands for pharmacophore generation to identify potential modulators of ABCC1 NBDs using both ligand (pharmacophore)- and structure (molecular docking)-based approaches

Objectives

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Results