Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

Molecules

Yoko Ogino¹  Yuri Shibasaki¹  Akira Sato¹  Kiyotaka Katsuragi¹  Fumiaki Uchiumi²  Sei-ichi Tanuma³  Miwa Okazawa³  Kosho Makino⁴  Hideyo Takahashi⁴  Miyuki Nomura⁵  Yoshimi Sakamoto⁵  Nobuhiro Tanuma⁵  Takahiro Oyama⁶  Hideaki Abe⁶  Hiroaki Yamazaki⁶  Atsushi Yoshimori⁷  Yasunobu Asawa⁸  Hiroyuki Nakamura⁸ 

[1] Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan;Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan;Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba 278-8510, Japan;Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan;Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan;Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo 102-0084, Japan;Institute for Theoretical Medicine Inc., Fujisawa, Kanagawa 251-0012, Japan;Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan;

关键词: nicotinamide phosphoribosyltransferase;    NAD⁺ biosynthesis;    inhibitor;    azacyclohexane;    anticancer drug;    drug design;   

DOI  :  10.3390/molecules25163633

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown