Quantitative structural assessments of potential meprin β inhibitors by non-linear QSAR approaches and validation by binding mode of interaction analysis

Abstract

The Zn²⁺-dependent endopeptidase meprin β is an astacin family metalloenzyme that belongs to the metzincin superclass of metalloproteases. The presence of a wide variety of meprin β substrates has enabled this metalloenzyme to influence a range of biological pathways and processes that correspondingly correlate meprin β with several diseases and abnormal physiological conditions. The influences of the meprin β proteolytic activity have been observed in cancer, neurodegenerative disorders, hyperkeratosis, and inflammatory conditions, including fibrosis. Therefore, the development of effective inhibitors is an achievable method for therapeutic advancement against meprin β-related pathophysiological conditions. In this context, in this study, a combined quantitative structural assessment of a set of meprin β inhibitors is performed via fragment-based non-linear pattern recognition techniques and the binding mode of interaction analysis at the active site of the enzyme. This study has elucidated various structural attributes such as the presence of a chiral center, the orientation of halogenic groups, hydroxyl and carbonyl functions, and the effect of aryl sulfonamide moieties along with their effect on the binding of these compounds at the active site. Depending on the present outcomes, some new molecules were designed and these were highly effective meprin β inhibitors. The molecular dynamics (MD) simulation study also revealed the stability of both the best active and the designed compound at the meprin β active site. Therefore, the findings of this current study as well as the developed non-linear machine learning (ML) models of these meprin β inhibitors can be a valuable tool to identify and design potent and effective inhibitors for the treatment of meprin β-related pathophysiological conditions.