Abstract
Breast cancer (Bc(a)) is the prominent, most commonly detected, and the leading cause of mortality among women. Estrogen receptor alpha (ER alpha) is considered an important receptor for the proliferation of this disease and its blockage is necessary for the treatment of Bc(a). The purpose of the current study is to design novel potential inhibitors against ER alpha of Bc(a). We designed modafinil drug derivatives using quantum chemical methods. These newly designed derivatives were put under an in-silico investigation followed by molecular docking simulation, molecular dynamics simulation, and MMPBSA analysis to find novel inhibitors of ER alpha. Moreover, three reference anticancer drugs; tamoxifen, raloxifene, and toremi-fene are also studied against ERa of Bca. The spectroscopic and structural features of sulfoxide-based designed derivatives of modafinil drug M1 ((R)-2-(banzhydrylsulfinyl-N,N diethylacetamide) have been evaluated using different quantum chemical analyses. The findings of the current investigation demonstrate that all studied ligands exhibit the binding energy ranges (-5.3 to-5.8 Kcal/mol). The designed compounds showed effective hydrophobic (alkyl, 7C-alkyl, 7C-sigma, 7C-amide stacked, 7C -7C T-shaped) interactions and hydrogen bond formation and are anticipated to be potential inhibitors against ERa. Additionally, designed derivatives have a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and drug-likeness properties obeying RO5 without any toxicity. The stability profile of designed derivatives (M1 -M6) was further validated by molecular dynamics (MD) simulation and calculate binding free energy by the MM-PBSA approach. All ligand-protein complexes showed structural stability over the 120 ns MD simulation time. The MD simulation of the complex system was carried out by RMSD (root-mean-square deviation) of C a atoms of ERa, RMSF (root mean square fluctuations), Rg (radius of gyration), SASA (solvent accessible surface area), and dynamic behavior of hydrogen bonds. The MD simulation results illustrate that RMSD for trajectories of designed derivative complexes over 120 ns are within the acceptable deviation range of similar to 3 A. The calculations of net binding free energy (delta G(bind)) between the designed derivatives and their complexes are found to be-8.50 Kcal/mol (M1) at maximum and-5.197 Kcal/mol (M3) at a minimum among all derivatives. The outcomes of our current in-silico investigation will evoke the scientific community to carry out further in vivo and in vitro studies on designed modafinil derivatives that can be potential therapeutic drug candidates against ERa.(c) 2022 Elsevier B.V. All rights reserved.