Development of Predictive GRIND Models to Probe Inhibitors Selectivity of Multidrug Efflux Transporters ABCB1 and ABCG2

Abstract

P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are transmembrane, AТРdependent drug efflux pumps that transport a wide variety of structurally and functionally diverse compounds out of cells. ABCB1 is expressed in epithelial cells of the liver, kidney, pancreas, intestine, as well as at the BBB thus, underscoring its role in maintaining concentration gradients of toxic compounds at physiological barriers. ABCG2 is also involved in normal physiological functions in the intestine. In addition, both transporters are very often overexpressed in tumor cells and thus, are one of the major factors responsible for multiple drug resistance (MDR) in antitumor therapy. Inhibition of one or the other transporter in different malignancies has been advocated as promising concept to overcome the MDR phenotype. Considerable overlap in modulators of certain anti targets such as promiscuous drug efflux transporters, the hERG and CYP450 produce side effects related to pharmacokinetics and thus, lead to late-stage failure of drugs. In this respect, a better understanding of the 3D structural requirements for selective inhibition of ABCB1 and ABCG2 is of high importance. Towards this goal, a highly selective data set of inhibitors of ABCB1 and ABCG2, including propafenone and tariquidar analogues respectively, has been used to perform GRID Independent Molecular Descriptors (GRIND) analysis. Our results demonstrate a dominant role of molecular shape in drug-ABCB1 interactions. Moreover, optimal distances of different pharmacophoric features from molecular boundaries of ABCB1 modulators advocate their selectivity. However, presence of two H-bond donors at a distance of 7.6-8 A° has been identified in the selective modulators of ABCG2. Furthermore, two H-bond acceptors at a distance of less than 10.0 A° contribute positively towards inhibition potencies of ABCG2 modulators. However, two Нbond acceptors at larger distance of 11.6-12 A° have been identified in most active inhibitors of ABCB1. Docking analysis of ABCB1 with selective modulators suggest propafenone binding at TМ5, TM6, TM7 and TM12 with amino acid Phe342, Phe335 and Phe334 and leu338 plays important role xii Abstract in ligand protein interaction. Conversely, His630 and Arg465 in ABCG2 contribute in hydrogen bonding with central ring and terminal methoxy groups of isoqunolines, respectively.