Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

Abstract

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

Biosynthesis of a Therapeutically Important Nicotinamide Mononucleotide through a Phosphoribosyl Pyrophosphate Synthetase 1 and 2 Engineered Strain of Escherichia coli

“…NMN is the intermediate product formed during NAD + biosynthesis using NAM as the substrate via the salvage pathway. NAMPT acts as a homodimer with two unique tunnel-shaped cavities adjacent to each active site at the dimer interface and catalyzes the rate-limiting primary step of the salvage pathway . Through this pathway, NAMPT transfers the phosphoribosyl residue from PRPP to NAM for NMN biosynthesis.…”

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

“…In silico 3D pharmacophore search was performed with LigandScout software [ 78 ]. All compounds were constructed by Chem-Draw Professional 18.0 and converted to 3D conformations by the optimization program in LigandScout software [ 59 , 79 , 80 ]. The degrees of 3D similarity of small molecular compounds are proportional to the calculated 3D PFS values, and the 0.5 threshold (half 3D similarity) is a good choice.…”

A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

“…In silico 3D pharmacophore similarity analyses were performed with LigandScout software [ 45 ]. All compounds were constructed by Chem-Draw Professional 18.0 and converted to 3D conformations by the optimization program in LigandScout software [ 46 , 47 ].…”