Abstract
The protein ATP-binding cassette subfamily G member 2 (ABCG2) is one of the major factors behind multidrug resistance (MDR) in breast cancer. We performed three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, docking, and molecular dynamics (MD) simulation to design pyrimidine-based ABCG2 antagonists. The developed QSAR model (r (2) = 0.92, q (2) = 0.82, and good cross-validated r (2) = 0.73) dictate requirement of electrostatic, and hydrophobic fields for modulating bioactivity. Based on this rationale, we designed and screened 1010 new compounds, among them 2 (ND-510 and ND-500) exhibit excellent drug-like features. Comparative molecular docking, MM/GBSA and ADMET profiles were determined to understand the interactive poses, affinity, and drug-likeness of the designed compounds. Furthermore, MD simulations were performed with the ABCG2 receptor, and the results were compared with the two earlier synthesized active compounds. The outcomes of the study will help researchers to develop new antagonists for treatment of MDR breast cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03231-1.