Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors

Journal of Molecular Modeling
Agnieszka A KaczorAntti Poso

Abstract

The endocannabinoid system remains an attractive molecular target for pharmacological intervention due to its roles in the central nervous system in learning, thinking, emotional function, regulation of food intake or pain sensation, as well as in the peripheral nervous system, where it modulates the action of cardiovascular, immune, metabolic or reproductive function. α/β hydrolase domain containing 6 (ABHD6)--an enzyme forming part of the endocannabinoid system--is a newly discovered post-genomic protein acting as a 2-AG (2-arachidonoylglycerol) serine hydrolase. We have recently reported a series of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. Here, we present comparative molecular field analysis (CoMFA) and molecular dynamics studies of these compounds. First, we performed a homology modeling study of ABHD6 based on the assumption that the catalytic triad of ABHD6 comprises Ser148-His306-Asp 278 and the oxyanion hole is formed by Met149 and Phe80. A total of 42 compounds was docked to the homology model using the Glide module from the Schrödinger suite of software and the selected docking poses were used for CoMFA alignment. A model with the following statistics was obtained: R(2) = 0.98, Q(2) = 0....Continue Reading

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Citations

Nov 2, 2019·Journal of Biomolecular Structure & Dynamics·Zhenhai PanMaosheng Cheng
Feb 3, 2018·Future Medicinal Chemistry·Marcelo T de Oliveira, Edson Katekawa
Sep 22, 2019·International Journal of Molecular Sciences·Agata ZiębaAgnieszka A Kaczor
Jul 10, 2020·Journal of Biomolecular Structure & Dynamics·Manish Kumar TripathiPunit Kaur
Oct 31, 2017·Journal of Biomolecular Structure & Dynamics·Wen-Qing JiaXian-Chao Cheng
Mar 27, 2018·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Agnieszka A KaczorDariusz Matosiuk
Mar 12, 2019·Trends in Pharmacological Sciences·Jessica K CaoNephi Stella
Jul 3, 2021·International Journal of Molecular Sciences·Agata ZiębaAgnieszka A Kaczor
Jul 3, 2021·Journal of Medicinal Chemistry·Giulia BononiCarlotta Granchi
Oct 28, 2021·Cannabis and Cannabinoid Research·Liting DengNephi Stella

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Software Mentioned

Studio
Glide
Discovery
LigPrep
Schrödinger Suite
Sybyl
Epik
CoMFA

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