<i>In‐Silico</i> Design of Novel Indole‐Selenide Derivatives as Potential P‐Glycoprotein Inhibitors Against Multi‐Drug Resistance in MCF‐7/ADR Cells: 2D‐QSAR, Molecular Docking, and Dynamics Simulations

Abstract In this work, a set of thirty‐one novel indole‐selenide derivatives ( C1 – C31 ), reported recently as P‐glycoprotein inhibitors against multi‐drug resistance in MCF‐7/ADR cells, have been computationally investigated for the first time by in‐silico approaches, combining 2D‐quantitative structure‐activity relationship based virtual screening (2D‐QSAR‐VS) model, molecular docking, and dynamics simulations. The in‐silico study aims to design new potent molecules with higher anticancer inhibitory activity than observed with in‐vitro assays. The 2D‐QSAR model is built using multiple linear regression (MLR) techniques, and cross‐validated by internal and external parameters, applicability domain (AD) analysis, and Y‐randomization tests, corroborating the Golbreikh and Tropsha criteria. Subsequently, virtual screening was performed on the generated database, considering higher pIC50 values than the most effective in‐vivo C27 inhibitor. Subsequently, molecular docking and dynamics simulations were applied on the selected higher‐scoring ligands showing the best interactions with the PHE643, TYR745, and PRO571 amino acids of the P‐gp receptor (7 A6E), predicting dynamically stable complexes at the time‐scale of 200 ns. The in‐silico outcomes indicate that the selected new ligands have shown promising inhibitory activity for future anti‐cancer therapies, with perspective validating by in‐vitro and in‐vivo studies.