Exploring crucial structural attributes of quinolinyl methoxyphenyl sulphonyl-based hydroxamate derivatives as ADAM17 inhibitors through classification-dependent molecular modelling approaches.

Abstract

A Disintegrin and Metalloproteinase 17 (ADAM17), a Zn²⁺-dependent metalloenzyme of the adamalysin family of the metzincin superfamily, is associated with various pathophysiological conditions including rheumatoid arthritis and cancer. However, no specific inhibitors have been marketed yet for ADAM17-related disorders. In this study, 94 quinolinyl methoxyphenyl sulphonyl-based hydroxamates as ADAM17 inhibitors were subjected to classification-based molecular modelling and binding pattern analysis to identify the significant structural attributes contributing to ADAM17 inhibition. The statistically validated classification-based models identified the importance of the P1' substituents such as the quinolinyl methoxyphenyl sulphonyl group of these compounds for occupying the S1' - S3' pocket of the enzyme. The quinolinyl function of these compounds was found to explore stable binding of the P1' substituents at the S1' - S3' pocket whereas the importance of the sulphonyl and the orientation of the P1' moiety also revealed stable binding. Based on the outcomes of the current study, four novel compounds of different classes were designed as promising ADAM17 inhibitors. These findings regarding the crucial structural aspects and binding patterns of ADAM17 inhibitors will aid the design and discovery of novel and effective ADAM17 inhibitors for therapeutic advancements of related diseases.