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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 fluorene as central core and lead 3 having phenyl-benzamide as a core showed stable moiety which was observed from electronic property analysis. Active site residual communication in identified leads bound complex also showed similarity to known inhibitor complexes. Compounds containing these moieties were not reported until now against NAMPT inhibition and can be considered as novel cores for future development of drugs to inhibit NAMPT function.