Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783577391828828160
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
work_keys_str_mv AT tanumaseiichi structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT katsuragikiyotaka structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT oyamatakahiro structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT yoshimoriatsushi structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT shibasakiyuri structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT asawayasunobu structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT yamazakihiroaki structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT makinokosho structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT okazawamiwa structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT oginoyoko structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT sakamotoyoshimi structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT nomuramiyuki structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT satoakira structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT abehideaki structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT nakamurahiroyuki structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT takahashihideyo structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT tanumanobuhiro structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors
AT uchiumifumiaki structuralbasisofbeneficialdesignforeffectivenicotinamidephosphoribosyltransferaseinhibitors