A combined ligand-based and structure-based in silico molecular modeling approach to pinpoint the key structural attributes of hydroxamate derivatives as promising meprin β inhibitors

Human meprin beta is a Zn2+-containing multidomain metalloprotease enzyme that belongs to the astacin family of the metzincin endopeptidase superfamily. Meprin beta, with its diverse tissue expression pattern and wide substrate specificity, plays a significant role in various biological processes, including regulation of IL-6R pathways, lung fibrosis, collagen deposition, cellular migration, neurotoxic amyloid beta levels, and inflammation. Again, meprin beta is involved in Alzheimer's disease, hyperkeratosis, glomerulonephritis, diabetic kidney injury, inflammatory bowel disease, and cancer. Despite a crucial role in diverse disease processes, no such promising inhibitors of meprin beta are marketed to date. Thus, it is an unmet requirement to find novel promising meprin beta inhibitors that hold promise as potential therapeutics. In this study, a series of arylsulfonamide and tertiary amine-based hydroxamate derivatives as meprin beta inhibitors has been analyzed through ligand-based and structure-based in silico approaches to pinpoint their structural and physiochemical requirements crucial for exerting higher inhibitory potential. This study identified different crucial structural features such as arylcarboxylic acid, sulfonamide, and arylsulfonamide moieties, as well as hydrogen bond donor and hydrophobicity, inevitable for exerting higher meprin beta inhibition, providing valuable insight for their further future development.