Harnessing high potential benzothiazole chalcones against dengue virus NS5 protein: A multi-faceted theoretical study through molecular docking, ADME, and DFT

Abstract

Chalcones bearing tetralone, indanone and benzothiazole cores were synthesized successfully using a general Claisen-Schmidt condensation protocol. The prepared compounds were purified and structurally analyzed by ¹H, ¹³C NMR, and FT-IR techniques. A multi-faceted theoretical approach, combining Density Functional Theory (DFT), molecular docking, and ADME predictions, was employed to evaluate their therapeutic potential. DFT calculations at the B3LYP/def2-TZVP level revealed key electronic properties, with TD3 compound demonstrating the highest chemical reactivity. Molecular Electrostatic Potential (MEP) and Reduced Density Gradient (RDG) analyses provided insights into the compounds' non-covalent interactions and charge distributions. Molecular docking studies against the NS5 protein (PDB: 6KR2) showed superior binding affinities for all three compounds compared to the control ligand SAH, with TD3 exhibiting the lowest binding energy (−8.41 kcal/mol) and theoretical inhibition constant (689.31 nM). ADME predictions indicated favorable drug-like properties with concerns regarding aqueous solubility and potential P-glycoprotein interactions. Toxicity evaluations highlighted challenges, particularly in hepatotoxicity and carcinogenicity. The study identified TD3 as a promising lead compound for Dengue Virus NS5 inhibition, while also emphasizing the need for targeted modifications to address toxicity concerns. This research not only contributes to anti-dengue drug discovery efforts but also provides a robust methodological framework for the theoretical evaluation of similar small compounds in future investigations.