A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors

Journal of Medicinal Chemistry
Daisuke TanakaNaoto Kusunose

Abstract

Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.

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Citations

Feb 26, 2013·Journal of Chemical Information and Modeling·Tian ZhuKirk E Hevener
Dec 16, 2011·Journal of Medicinal Chemistry·Hong C Shen, Bruce D Hammock
Jan 8, 2014·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Mohammad K MohammadiRamin Miri
Jul 19, 2013·Future Medicinal Chemistry·Dalia I HammoudehRichard E Lee
Jul 23, 2015·Chemical Biology & Drug Design·Jiazhong LiPaola Gramatica
Aug 16, 2012·Medicinal Research Reviews·Mohammed Naseer Ahmed KhanNaoki Miyata
Feb 18, 2016·Journal of Chemical Information and Modeling·Birgit WaltenbergerHermann Stuppner
Apr 5, 2017·Journal of Medicinal Chemistry·Ignacio AliagasMarian C Bryan
Jun 3, 2020·Archiv der Pharmazie·Iman MahloojiSayyed Abbas Tabatabai
Nov 9, 2019·Journal of Biomolecular Structure & Dynamics·Sudha Bhagwati, Mohammad Imran Siddiqi
Jan 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ram B KhattriThomas C Leeper
Sep 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hong Xu LiWei Li
Dec 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Amarjyoti Das MahapatraBhaskar Datta
Jan 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Li Shi, Naixia Zhang
Jun 4, 2021·Drug Discovery Today·Maria BzówkaArtur Góra
Jul 26, 2012·Journal of Medicinal Chemistry·Gerard J P van WestenAndreas Bender
Feb 5, 2014·Journal of Chemical Information and Modeling·Diane Joseph-McCarthyDemetri Moustakas

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