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Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors
Sei-Ichi Tanuma1,2, Kiyotaka Katsuragi2, Takahiro Oyama3
1Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
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.
Insights
New nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, 3a and 3b, were developed. Compound 3a shows superior enzyme inhibition and cellular potency compared to 3b and FK866, highlighting the importance of minimizing His191 interactions.
Area of Science:
- Medicinal Chemistry
- Cancer Metabolism
- Enzyme Inhibition
Background:
- Nicotinamide phosphoribosyltransferase (NAMPT) inhibition is a promising cancer therapy.
- Existing NAMPT inhibitors face challenges with cytotoxicity and resistance.
- Novel inhibitors are needed to overcome these limitations.
Purpose of the Study:
- To design and synthesize novel NAMPT inhibitors with improved efficacy and safety.
- To investigate the structure-activity relationships of new azaindole-piperidine and azaindole-piperazine analogues.
- To understand the molecular basis for differential potency among inhibitors.
Main Methods:
- Synthesis of azaindole-piperidine (3a) and azaindole-piperazine (3b) analogues.
- Enzyme inhibition assays to determine inhibitory activity.
- Cellular potency assays to evaluate efficacy in cancer cells.
- In silico binding mode analysis to predict interactions within the NAMPT active site.
Main Results:
- Compound 3a demonstrated significantly higher enzyme inhibitory activity and cellular potency than 3b and the reference inhibitor FK866.
- In silico analysis revealed electronic repulsion between 3b's piperazine nitrogen and His191 as a key factor in reduced binding affinity.
- 3a exhibited a stronger binding affinity score compared to 3b, despite similar conformations.
Conclusions:
- Minimizing electrostatic interactions with His191 is crucial for designing effective NAMPT inhibitors.
- Electrostatic enthalpy potential, not entropy, significantly influences binding affinity and inhibitor potency.
- The findings provide valuable insights for the rational design of next-generation NAMPT-targeting cancer therapeutics.
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