Structure-based virtual screening, molecular dynamics simulation and in vitro evaluation to identify inhibitors against NAMPT

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a bottleneck enzyme that plays a key role in recycling nicotinamide to maintain the adequate NAD + level inside the cell. It involves maintaining the cellular bioenergetics and providing a necessary substrate for functions essential to rapidly proliferating the cancer cells. Therefore, inhibition of NAMPT appears as a therapeutic potential for cancer treatment. Here, the vast virtual screening followed by focused docking and in-vitro analysis was carried out to identify the promising hits of NAMPT. We have identified two potential hits from the filtered molecules, which are chemically diverse and have shown comparable quantitative values with reported co-crystal ‘1QS’ as their binding pattern matched nicely. These two compounds are further explored through molecular dynamics simulations (MD) combined with pharmacokinetics profiling and thermodynamic analysis demonstrating their suitability as novel NAMPT inhibitors that can be used as starting points for a hit-to-lead campaign.

Communicated by Ramaswamy H. Sarma

Keywords:

• NAMPT
• virtual screening
• molecular dynamics
• MM-GBSA
• MTT assay

Acknowledgements

The authors acknowledge the anonymous reviewer for their helpful recommendations and remarks, which have improved the manuscript's content and presentation.

Disclosure statement

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

Author's contribution

S. Asthana proposed and designed the study. S. Panwar, A. Kumari, H.K Saini, and A.K. Tiwari performed experiments and analysis of results. S. Panwar, A. Kumari, and S. Asthana wrote the manuscript. P Tripathi proposed the in-vitro studies.

Additional information

Funding

The work has been supported by the THSTI.