Identification of novel Nicotinamide Phosphoribosyltransferase (NAMPT) inhibitors using computational approaches

Journal of Biomolecular Structure & Dynamics
Manish KesherwaniDevadasan Velmurugan

Abstract

Nicotinamide Phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of NAD. Cancer cells have elevated poly [ADP-Ribose] polymerase 1 (PARP) activity as well as the immense necessity of ATP: thereby consuming NAD at a higher rate than normal tissues. The perturbation of these intracellular processes is more sensitive and highly dependent on NAMPT to maintain the required NAD levels. Functional inhibition of NAMPT is, therefore, a promising drug target in therapeutic oncology. In this study, the importance of intermolecular contacts was realized based on contact occupancy and favorable energetic from molecular dynamic simulation to discern non-critical contacts of four different classes of potential NAMPT inhibitor bound complexes. Further, pharmacophore modeling, molecular docking, a quantum mechanical properties and MD simulation, as well as active site residual network communication were employed to identify potential leads. Present studies identified two leads, 2 and 3 which have better binding free energy compared to known inhibitors and showed stable hydrogen bonding and hydrophobic contacts with β barrel cavity lining residues in the active site of the dimer interface (A'B). Lead 2 containing fluo...Continue Reading

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Datasets Mentioned

BETA
GMX1778

Software Mentioned

NAMPT
AMBER
Amber12
Gaussian g03
Glide
NVT
Small
MMPBSA
Molecule Drug Discovery Suite
General Amber GAFF

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