Next Article in Journal
The Fuzziness in Molecular, Supramolecular, and Systems Chemistry
Next Article in Special Issue
The Potential Role of Cathepsin K in Non-Small Cell Lung Cancer
Previous Article in Journal
Multiple-Reaction Monitoring Tandem Mass Method for Determination of Phenolics and Water-Soluble Vitamins in Eccoilopus formosanus
Previous Article in Special Issue
Standardized Saponin Extract from Baiye No.1 Tea (Camellia sinensis) Flowers Induced S Phase Cell Cycle Arrest and Apoptosis via AKT-MDM2-p53 Signaling Pathway in Ovarian Cancer Cells
Open AccessArticle

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

1
Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba 278-8510, Japan
2
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
3
Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo 102-0084, Japan
4
Institute for Theoretical Medicine Inc., Fujisawa, Kanagawa 251-0012, Japan
5
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan
6
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
7
Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan
8
Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Marialuigia Fantacuzzi and Alessandra Ammazzalorso
Molecules 2020, 25(16), 3633; https://doi.org/10.3390/molecules25163633
Received: 22 July 2020 / Revised: 6 August 2020 / Accepted: 6 August 2020 / Published: 10 August 2020
(This article belongs to the Special Issue Anticancer 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 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. View Full-Text
Keywords: nicotinamide phosphoribosyltransferase; NAD+ biosynthesis; inhibitor; azacyclohexane; anticancer drug; drug design; enthalpy effect nicotinamide phosphoribosyltransferase; NAD+ biosynthesis; inhibitor; azacyclohexane; anticancer drug; drug design; enthalpy effect
Show Figures

Graphical abstract

MDPI and ACS Style

Tanuma, S.-I.; Katsuragi, K.; Oyama, T.; Yoshimori, A.; Shibasaki, Y.; Asawa, Y.; Yamazaki, H.; Makino, K.; Okazawa, M.; Ogino, Y.; Sakamoto, Y.; Nomura, M.; Sato, A.; Abe, H.; Nakamura, H.; Takahashi, H.; Tanuma, N.; Uchiumi, F. Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors. Molecules 2020, 25, 3633.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop