Docking Study, ADMET Profiling of the Designed 3-Chlorobenzo[b]thiophene-2-Carbonyl Chloride Derivatives: Promising Anti-Breast Cancer Activity

Abstract

Globally, breast cancer accounted for approximately 700٫000 deaths in 2020. Estrogen receptor alpha (ERα) is the primary pathway for breast cancer treatment. Tamoxifen (TAM) is the most extensively used drug for estrogen receptor (+) breast cancer. However, it is implicated in endometrial carcinoma, pulmonary thrombus, stroke, and breast cancer resistance. This research aims to overcome these issues in selectivity and side effects. The study was conducted in a new drug design using Structure Based Drug Design (SBDD) approach, molecular docking with ERα and then predicting their ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile. GOLD (Genetic Optimization for Ligand Docking, v.5.7.1), SwissADME and BIOVIA Discovery Studio Visualizer 2020 applications used for the predicting and analyzing of the results. It has shown that all of our compounds (MFA1-8) where a higher PLP (the Piecewise Linear Potential) fitness scores with a range (66.21-77.20) than (60.96) for TAM with different molecular interactions such as H- bondings and non-covalent hydrophobic interactions with the pose. They were all exhibited better conformation to prevent helix-12 (H-12) from repositioning over the opening of the binding pocket. This work generated fresh insight into the significant hydrophobic bonding with LEU428. MFA1-8 showed better pharmacokinetics, drug-likeness, and toxicity profiles than TAM. These findings suggest that these novel 3-chlorobenzo[b]thiophene-2-carbonyl chloride derivatives could serve as the lead compounds to fight breast cancer by inhibiting the ERα pathway.