Shedding light on designing potential meprin β inhibitors through ligand-based robust validated computational approaches: A proposal to chemists!

Abstract

Human meprin (EC 3.4.24.18) is a member of the metzincin superfamily. It correlates with matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinase). Overexpression of meprin β is implicated in fibrosis, inflammatory diseases and cancers. However, selective meprin β inhibition is crucial to reduce cancer metastasis and adverse effects in inflammation. It also plays critical roles in modulating several interleukins and growth factors. Moreover, meprin β cleaves amyloid precursor protein, thought to be involved in the progression of Alzheimer’s disease. Therefore, meprin β inhibitors are considered to be emerging therapeutics with paramount importance in the treatment of kidney failure, fibrosis, inflammatory bowel diseases and cancer. Despite its crucial implication in several diseases, no meprin β inhibitors are available as drug candidates till date. Therefore, it is an urgent need to identify new potential meprin β inhibitors as prospective therapeutics. In this article, a series of meprin β inhibitors has been analysed through multiple molecular modelling studies as the first initiative to get an idea about their structural, physicochemical and pharmacophoric requirements for higher activity. All in silico approaches performed here are statistically validated and subsequently adjudicated each other. Compounds with p-carboxylic acid substituted arylsulphonamide moiety attached with m-carboxylic acid substituted benzyl group along with a methylene hydroxamate function may be crucial for imparting potential meprin β inhibition. Depending on the results obtained, 14 molecules have been proposed by QSAR model that predicted a minimum of 4-fold higher activity compared to these compounds of the current study.

Keywords:

• meprin β inhibitor
• QSAR
• Bayesian model
• KPLS
• pharmacophore mapping
• CoMSIA
• predicted activity

Acknowledgments

NA is thankful to University Grants Commission (UGC), New Delhi for providing Rajiv Gandhi National Fellowship (RGNF). We also thank the support from Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India and Department of Pharmacy, BITS-Pilani, Hyderabad Campus, India for providing the research facilities.