Structural exploration of arylsulfonamide-based ADAM17 inhibitors through validated comparative multi-QSAR modelling studies.

Abstract Zinc-dependent ADAM17 takes part in a number of life-threatening conditions such as inflammatory diseases, cancer, Alzheimer's disease and rheumatoid arthritis. Therefore, ADAM17 may be a valuable target to design specific inhibitors for combating these diseases. In this scenario, it is a challenging task to design specific ADAM17 inhibitors as none of the earlier investigated compounds has come into the market as a potential drug candidate. Here, molecular modelling including 2D-QSAR, HQSAR, Bayesian classification, pharmacophore mapping and molecular docking studies of arylsulfonamides were performed to explore the structural and pharmacophoric requirements for exerting higher ADAM17 inhibitory activity. All these molecular modelling approaches were validated individually and these were statistically significant and reliable. The bulky steric and hydrophobic P1′ substituents at the para position of the arylsulfonamido moiety favoured ADAM17 inhibition that supported and validated by molecular docking study. These crucial observations of arylsulfonamides may be considered for designing higher effective ADAM17 inhibitors in future. Graphical abstract Image 1 Highlights • Targeting ADAM17 enzyme may be a valuable weapon to combat inflammatory diseases, cancer, Alzheimer's disease and rheumatoid arthritis. • None of the ADAM17 inhibitors has come into the market as drug candidate till now. • Multi-QSAR modelling studies and molecular docking study were performed on arylsulfonamide-based ADAM17 inhibitors. • This study may be beneficial in designing potent ADAM17 inhibitors in future. [ABSTRACT FROM AUTHOR]