Background: ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1)
and breast cancer resistance protein (BCRP/ABCG2) are major determinants of pharmacokinetic,
safety and efficacy profiles of drugs thereby effluxing a broad range of endogenous substances across
the plasma membrane. Overexpression of these transporters in various tumors is also implicated in the
development of multidrug resistance (MDR) and thus, hampers the success of cancer chemotherapy.
Modulators of these efflux transporters in combination with chemotherapeutics could be a promising
concept to increase the effective intracellular concentration of anticancer drugs. However, broad and
overlapped specificity for substrates and modulators of ABCB1 and ABCG2, merely induce toxicity
and unwanted drug-drug interactions and thus, lead to late-stage failure of drugs.
Objective: In present investigation, we aim to identify specific 3D structural requirements for selective
inhibition of ABCB1 and ABCG2 transport function.
Method: GRID Independent Molecular Descriptor (GRIND) models of selective inhibitors of both
transporters have been developed, using their most probable binding conformations obtained from
molecular docking protocol.
Results: Our results demonstrated a dominant role of molecular shape and different H-bonding patterns
in drug-ABCB1/ABCG2 selective interactions. Moreover, distinct distances of different pharmacophoric
features from steric hot spots of the molecules provided a strong basis of selectivity for
both transporters. Additionally, our results suggested the presence of two H-bond donors at a distance
of 8.4-8.8 Å in selective modulators of ABCG2.
Conclusion: Our findings concluded that molecular shape along with three dimensional pattern of Hbonding
in MDR modulators play a critical role in determining the selectivity between the two targets.