Fakhar, Z, Hejazi, L, Tabatabai, SA et al. (1 more author) (2021) Discovery of novel heterocyclic amide-based inhibitors: an integrative in-silico approach to targeting soluble epoxide hydrolase. Journal of Biomolecular Structure and Dynamics, 40 (15). pp. 7114-7128. ISSN 0739-1102
Abstract
Inhibition of soluble epoxide hydrolase (sEH) is considered as an emerging druggable target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. Despite the availability of different classes of sEH small molecule inhibitors for the potential treatment of hypertension, only a few candidates have reached clinical trials, making the optimal control of blood pressure presently unattainable. This necessity motivated us to explore a series of novel quinazoline-4(3H)-one and 4,6-disubstituted pyridin-2(1H)-one derivatives targeting sEH enzyme. Herein, comprehensive computational investigations were performed to probe the inhibition efficacy of these potent compounds in terms of inhibitor-enzyme interactions against sEH. In this study, the 39 in-house with a focused library comprising 39 in-house synthesized compounds were selected. The structure-based pharmacophore modeling was developed based on the crystal structure of sEH with its co-crystallized biologically active inhibitor. The generated hypotheses were applied for virtual screening-based PHASE fitness scores. Docking-based virtual screening workflows were used to generate lead compounds using HTVS, SP and XP based GLIDE G-score values. The candidate leads were filtered using ADMET pharmacological and physicochemical properties screening. A 100-ns of molecular dynamics simulations with Molecular dynamics simulations (100 ns) were performed to explore the binding affinities of the considered compounds. Our study identified four best candidates from quinazoline-4(3H)-one derivatives, which indicated that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule sEH inhibitors.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Ⓒ2021 Informa UK Limited, trading as Taylor & Francis Group. This is an author produced version of an article published in Journal of Biomolecular Structure and Dynamics. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Soluble epoxide hydrolase; quinazoline-4(3H)-ones; pharmacophore modeling; docking workflow; ADMET; MD simulations |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Physical Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 21 Jun 2023 14:36 |
Last Modified: | 21 Jun 2023 17:55 |
Status: | Published |
Publisher: | Taylor and Francis |
Identification Number: | 10.1080/07391102.2021.1894987 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:200670 |