Investigation of 1H-1,2,3-triazole derivatives as TGF-β pathway targeted therapeutics for oral squamous cell carcinoma: an in-silico approach

Oral Squamous Cell Carcinoma (OSCC) is a predominant malignancy of the oral cavity characterized by poor prognosis, underscoring an urgent need for development of targeted therapeutic strategies. The TGF-β signaling pathway plays a critical role in progression of OSCC and represents a potential therapeutic target. Targeted inhibition of TGF-β signaling has recently attracted attention in drug discovery research, as eight TGF-β inhibitors are currently undergoing clinical trials by several pharmaceutical industries worldwide. In the current study a selected library of fifteen 1H -1,2,3-Triazole Derivatives screened against TGF- βI (PDB: 1PY5) through an in-silico drug discovery workflow combining molecular docking, density functional theory, molecular dynamics simulations, and MMPBSA analysis. Compounds 1-benzyl-5-(naphthalen-1-yl)-1 H -1,2,3-triazol-4-yl)(4-nitrophenyl)methanone ( Compound 3e ) and 5-(naphthalen-1-yl)-1-(4-nitrobenzyl)-1 H -1,2,3-triazol-4-yl)(phenyl)methanone ( compound 3o ) showed best docking score of -12.1 kcal/mol. Both ligands, through their functional groups, exhibited stable binding via multiple non-covalent interactions. Electrostatic potential mapping validated hydrogen bond formation with functional groups of lead compounds. Subsequently, favourable results for lead compounds confirmed stability of protein throughout simulation of 500 ns. Altogether, present study identified compound 3e and compound 3o as potential drug candidate for treatment of OSCC.