Identification of novel human nicotinamide N-methyltransferase inhibitors: a structure-based pharmacophore modeling and molecular dynamics approach

Abstract

Human nicotinamide N-methyltransferase (hNNMT) is a cytosolic enzyme associated in the phase-II metabolism, belonging to the S-adenosyl-L-methionine (SAM)-dependent methyltransferases family. Overexpression of hNNMT was observed in diseases such as metabolic disorders and different types of cancers, which suggest NNMT as a prospective therapeutic target. In this study we propose a structure-based pharmacophore model to understand the structural features responsible for the pharmacological activity. The generated model was validated using the ROC curve (AUC), goodness of hit score (GH), specificity, sensitivity and enrichment factor (EF). The pharmacophore was employed to retrieve active molecules from the ZINC database, followed by virtual-screening and molecular docking. Six molecules with the best pharmfit score, binding energy and ADMET properties were identified in this study. A 150 ns molecular dynamics simulation was performed on the selected molecules complexed with hNNMT protein to validate the results. The molecules ZINC35464499, ZINC13311192, ZINC31159282, ZINC14650833, ZINC14819515 and ZINC00303881 were identified, which could be act as the potential hNNMT inhibitors and can also be used as direct hits for developing novel hNNMT antagonists.

Communicated by Ramaswamy H. Sarma

Keywords:

• Virtual-screening
• pharmacophore modeling
• NNMT inhibitor
• cancer
• diabetes
• molecular docking
• ADMET
• molecular dynamics simulation

Acknowledgements

We thank High Performance Computing Facility (HPCE) and Indian Institute of Technology Madras for computational facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Ministry of Human Resource and Development, Govt. of India [grant number SB/2021/0792/CYMHRD/008189]