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

The ATP-binding cassette (ABC) 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 (BCRP) 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, substrates and inhibitors molecular binding 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 bound membrane. Further, the binding affinities of compounds were estimated by free binding energy employing MM-GBSA. Docking results show three compounds, Docetaxel > Tariquidar > Tezacaftor having 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. 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. Hence, Tariquidar could serve as a potential candidate for the design of highly efficient inhibitors targeting ABCG2 in breast cancer therapy.