Elucidating the binding specificity of interactive compounds targeting ATP-binding cassette subfamily G member 2 (ABCG2).

The ATP-binding cassette transporter superfamily plays a pivotal role in cellular detoxification and drug efflux. ATP-binding cassette subfamily G member 2 (ABCG2) referred to as the Breast cancer resistance protein has emerged as a key member involved in multidrug resistance displayed by cancer cells. Understanding the molecular basis of substrate and inhibitor recognition, and binding within the transmembrane domain of ABCG2 is crucial for the development of effective therapeutic strategies. Herein, utilizing state-of-the-art molecular docking algorithms and molecular dynamic (MD) simulations, molecular binding of substrates and inhibitors with ABCG2 are defined, distinctly. We performed extensive virtual screening of Drugbank to identify the potential candidates, and MD simulations of docked complexes were carried out in POPC lipid bilayer. Further, the binding affinities of compounds were estimated by free binding energy employing MM-GBSA. To gain deeper insight into the binding affinities and molecular characteristics contributing to inhibitory potential of certain substrates, we included some well-known inhibitors, like Imatinib, Tariquidar, and Ko 143, in our analysis. Docking results show three compounds, Docetaxel > Tariquidar > Tezacaftor having the highest binding affinities (≤ 12.00 kcal/mol) for ABCG2. Remarkably, MM-GBSA results suggest the most stable binding of Tariquidar with ABCG2 as compared to the other inhibitors. Furthermore, our results suggested that Docetaxel, Ozanimod, Pitavastatin, and Tezacaftor have the strongest affinity for the drug-binding site(s) of ABCG2. These results provide valuable insights into the key residues that may govern substrate/inhibitor recognition, shedding light on the molecular determinants influencing substrate specificity, transport kinetics, and ABCG2-mediated drug efflux.