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Ligand-based in silico identification and biological evaluation of potential inhibitors of nicotinamide N-methyltransferase

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Abstract

Nicotinamide N-methyltransferase (NNMT) is a protein coding gene, which methylates the nicotinamide (NA) (vitamin B3) to produce 1-methylnicotinamide (MNA). Several studies have suggested that the overexpression of NNMT is associated with different metabolic disorders like obesity and type-2 diabetes thereby making it an important therapeutic target for development of anti-diabetic agents. Here we describe a workflow for identification of new inhibitors of NNMT from a library of small molecules. In this study, we have hypothesized a four-point pharmacophore model based on the pharmacophoric features of reported NNMT inhibitors in the literature. The statistically significant pharmacophore hypothesis was used to explore the Maybridge compound library that resulted in mapping of 1330 hit compounds on the proposed hypothesis. Subsequently, a total of eight high scoring compounds, showing good protein–ligand interactions in the molecular docking study, were selected for biological evaluation of NNMT activity. Eventually, four compounds were found to show significant inhibitory activity for NNMT and can be further explored to design new derivatives around the identified scaffolds with improved activities as NNMT inhibitors.

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Acknowledgements

UK and LP acknowledge University Grant Commission (UGC), New Delhi, India, for providing fellowship, Chemical repository of CSIR-Central Drug Research Institute is acknowledged for providing Compounds from Maybridge library for in vitro biological evaluation. Department of Biotechnology (DBT), Ministry of Science and Technology Government of India (Grant No. GAP0384) is also gratefully acknowledged for funding this work. This manuscript has CSIR-CDRI manuscript number 10425.

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Authors and Affiliations

  1. Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Unnati Kushavah, Lalita Panigrahi, Shakil Ahmed & Mohammad Imran Siddiqi

  2. Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute Campus, Lucknow, India

    Unnati Kushavah & Mohammad Imran Siddiqi

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  1. Unnati Kushavah
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  2. Lalita Panigrahi
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  4. Mohammad Imran Siddiqi
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Correspondence to Mohammad Imran Siddiqi.

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Kushavah, U., Panigrahi, L., Ahmed, S. et al. Ligand-based in silico identification and biological evaluation of potential inhibitors of nicotinamide N-methyltransferase. Mol Divers 27, 1255–1269 (2023). https://doi.org/10.1007/s11030-022-10485-7

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  • DOI: https://doi.org/10.1007/s11030-022-10485-7

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