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Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors
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 homodim...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464552/ https://www.ncbi.nlm.nih.gov/pubmed/32785052 http://dx.doi.org/10.3390/molecules25163633 |
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author | Tanuma, Sei-ichi Katsuragi, Kiyotaka Oyama, Takahiro Yoshimori, Atsushi Shibasaki, Yuri Asawa, Yasunobu Yamazaki, Hiroaki Makino, Kosho Okazawa, Miwa Ogino, Yoko Sakamoto, Yoshimi Nomura, Miyuki Sato, Akira Abe, Hideaki Nakamura, Hiroyuki Takahashi, Hideyo Tanuma, Nobuhiro Uchiumi, Fumiaki |
author_facet | Tanuma, Sei-ichi Katsuragi, Kiyotaka Oyama, Takahiro Yoshimori, Atsushi Shibasaki, Yuri Asawa, Yasunobu Yamazaki, Hiroaki Makino, Kosho Okazawa, Miwa Ogino, Yoko Sakamoto, Yoshimi Nomura, Miyuki Sato, Akira Abe, Hideaki Nakamura, Hiroyuki Takahashi, Hideyo Tanuma, Nobuhiro Uchiumi, Fumiaki |
author_sort | Tanuma, Sei-ichi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7464552 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74645522020-09-04 Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors Tanuma, Sei-ichi Katsuragi, Kiyotaka Oyama, Takahiro Yoshimori, Atsushi Shibasaki, Yuri Asawa, Yasunobu Yamazaki, Hiroaki Makino, Kosho Okazawa, Miwa Ogino, Yoko Sakamoto, Yoshimi Nomura, Miyuki Sato, Akira Abe, Hideaki Nakamura, Hiroyuki Takahashi, Hideyo Tanuma, Nobuhiro Uchiumi, Fumiaki Molecules Article 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. MDPI 2020-08-10 /pmc/articles/PMC7464552/ /pubmed/32785052 http://dx.doi.org/10.3390/molecules25163633 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tanuma, Sei-ichi Katsuragi, Kiyotaka Oyama, Takahiro Yoshimori, Atsushi Shibasaki, Yuri Asawa, Yasunobu Yamazaki, Hiroaki Makino, Kosho Okazawa, Miwa Ogino, Yoko Sakamoto, Yoshimi Nomura, Miyuki Sato, Akira Abe, Hideaki Nakamura, Hiroyuki Takahashi, Hideyo Tanuma, Nobuhiro Uchiumi, Fumiaki Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title | Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title_full | Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title_fullStr | Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title_full_unstemmed | Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title_short | Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors |
title_sort | structural basis of beneficial design for effective nicotinamide phosphoribosyltransferase inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464552/ https://www.ncbi.nlm.nih.gov/pubmed/32785052 http://dx.doi.org/10.3390/molecules25163633 |
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