Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions

Akari Ikeda; Eishi Funakoshi; Mitsugu Araki; Biao Ma; Yukiko Karuo; Atsushi Tarui; Kazuyuki Sato; Yasushi Okuno; Kentaro Kawai; Masaaki Omote

doi:10.1016/j.bmc.2019.03.021

Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions

Bioorg Med Chem. 2019 May 1;27(9):1789-1794. doi: 10.1016/j.bmc.2019.03.021. Epub 2019 Mar 14.

Authors

Akari Ikeda¹, Eishi Funakoshi², Mitsugu Araki³, Biao Ma⁴, Yukiko Karuo⁵, Atsushi Tarui⁵, Kazuyuki Sato⁵, Yasushi Okuno³, Kentaro Kawai⁵, Masaaki Omote⁶

Affiliations

¹ Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
² Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanaka-machi, Neyagawa, Osaka 573-8508, Japan.
³ Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
⁴ Research and Development Group for In Silico Drug Discovery, Center for Cluster Development and Coordination (CCD), Foundation for Biomedical Research and Innovation at Kobe (FBRI), 6-3-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
⁵ Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
⁶ Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: omote@pharm.setsunan.ac.jp.

PMID: 30898436
DOI: 10.1016/j.bmc.2019.03.021

Abstract

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were -13.80 kcal/mol for COX-1 and -18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.

Keywords: (E)-trimethyl (3,3,3-trifluoroprop-1-enyl)silane; 3,3,3-Trifluoroprop-1-enyl group; COX-2 selective inhibition; Indomethacin; van der Waals contribution.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / metabolism
Indomethacin / chemistry*
Indomethacin / metabolism
Molecular Dynamics Simulation
Protein Structure, Tertiary
Static Electricity

Substances

Cyclooxygenase 2 Inhibitors
Cyclooxygenase 1
Cyclooxygenase 2
Indomethacin