In silico drug repurposing and lipid bilayer molecular dynamics puzzled out potential breast cancer resistance protein (BCRP/ABCG2) inhibitors

Abstract

Multidrug resistance (MDR) is a fundamental reason for the fiasco of carcinoma chemotherapy. A wide variety of anticarcinoma drugs are expelled from neoplasm cells through the ATP-binding cassette (ABC) transporter superfamily, rendering the neoplasm cells resistant to treatment. The ATP-binding cassette transporter G2 (ABCG2, gene symbol BCRP) is an ABC efflux transporter that plays a key function in MDR to antineoplastic therapies. For these reasons, the identification of medicaments as BCRP inhibitors could assist in discovering better curative approaches for breast cancer therapy. Because of the deficiency of prospective BCRP inhibitors, the SuperDRUG2 database was virtually screened for inhibitor activity towards the BCRP transporter using molecular docking computations. The most potent drug candidates were then characterized utilizing molecular dynamics (MD) simulations. Furthermore, molecular mechanics-generalized Born surface area (MM-GBSA) binding affinities of the most potent drug candidates were estimated. Based on the MM-GBSA binding affinities throughout 150 ns MD simulations, three drugs—namely zotarolimus (SD002595), temsirolimus (SD003393), and glecaprevir (SD006009)—revealed greater binding affinities towards BCRP transporter compared to the co-crystallized BWQ ligand with ΔG binding values of –86.6 ± 5.6, –79.5 ± 8.0, –75.8 ± 4.6 and –59.5 ± 4.1 kcal/mol, respectively. The steadiness of these promising drugs bound with BCRP transporter was examined utilizing their structural and energetical analyses throughout a 150 ns MD simulation. To imitate the physiological environment, 150 ns MD simulations for the identified drugs bound with BCRP transporter were conducted in the 1-palmitoyl-2-oleoyl-phosphatidylcholine lipid bilayer. These findings identify zotarolimus, temsirolimus and glecaprevir as auspicious anti-MDR drug leads that warrant further experimental assays. Communicated by Ramaswamy H. Sarma