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

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

Journal

Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298

Informations de publication

Date de publication:
01 05 2019
Historique:
received: 18 01 2019
revised: 08 03 2019
accepted: 09 03 2019
pubmed: 23 3 2019
medline: 23 2 2020
entrez: 23 3 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bmc.2019.03.021 PMID: 30898436
pubmed: 30898436
pii: S0968-0896(19)30095-1
doi: 10.1016/j.bmc.2019.03.021
pii:
doi:

Substances chimiques

Cyclooxygenase 2 Inhibitors 0
Cyclooxygenase 1 EC 1.14.99.1
Cyclooxygenase 2 EC 1.14.99.1
Indomethacin XXE1CET956

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1789-1794

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Akari Ikeda (A)

Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

Eishi Funakoshi (E)

Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanaka-machi, Neyagawa, Osaka 573-8508, Japan.

Mitsugu Araki (M)

Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.

Biao Ma (B)

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.

Yukiko Karuo (Y)

Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.

Atsushi Tarui (A)

Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.

Kazuyuki Sato (K)

Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.

Yasushi Okuno (Y)

Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.

Kentaro Kawai (K)

Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.

Masaaki Omote (M)

Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: omote@pharm.setsunan.ac.jp.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Structural modification of indomethacin toward...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Cyclooxygenase 1 › Structural modification of indomethacin toward...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Cyclooxygenase 2 › Structural modification of indomethacin toward...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antirhumatismaux › Anti-inflammatoires non stéroïdiens › Inhibiteurs des cyclooxygénases › Inhibiteurs de la cyclooxygénase 2 › Structural modification of indomethacin toward...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Indométacine › Structural modification of indomethacin toward...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Structural modification of indomethacin toward...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Structural modification of indomethacin toward...
questionsmedicales.fr › Phénomènes physiques › Phénomènes magnétiques › Phénomènes électromagnétiques › Électricité › Électricité statique › Structural modification of indomethacin toward...