Structure-based virtual screening, molecular dynamics simulation and <i>in vitro</i> 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 <i>in-vitro</i> analysis was carried out to identify the promising <i>hits</i> 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 <i>hit-to-lead</i> campaign.Communicated by Ramaswamy H. Sarma.