2019
DOI: 10.1016/j.bmcl.2018.11.019
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Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments

Abstract: Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors.

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Cited by 21 publications
(15 citation statements)
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References 17 publications
(26 reference statements)
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“…Historically, most covalent inhibitors were designed by the addition of an electrophile to an already known reversible inhibitor that suitably binds next to a cysteine residue (Angst et al, 2020;Dubiella et al, 2015;Hagel et al, 2015;Vazquez-Rodriguez and Wright, 2019;Ward et al, 2015;Weisner et al, 2015). More recently, covalent inhibitors are also being discovered by empirical screening of covalent fragment libraries (Backus et al, 2016;Craven et al, 2018;Johansson et al, 2019;Kathman et al, 2014Kathman et al, , 2015Parker et al, 2017;Resnick et al, 2019) and by covalent virtual screening (Bensinger et al, 2019;Chowdhury et al, 2019;London et al, 2014;Nnadi et al, 2018;Rachman et al, 2019;Scarpino et al, 2018;Shraga et al, 2019;Toledo Warshaviak et al, 2014). While covalent fragment and virtual screening can potentially discover new scaffolds, the binding affinity of primary hits may be relatively low, and often require laborious medicinal chemistry to reach suitable potency.…”
Section: Introductionmentioning
confidence: 99%
“…Historically, most covalent inhibitors were designed by the addition of an electrophile to an already known reversible inhibitor that suitably binds next to a cysteine residue (Angst et al, 2020;Dubiella et al, 2015;Hagel et al, 2015;Vazquez-Rodriguez and Wright, 2019;Ward et al, 2015;Weisner et al, 2015). More recently, covalent inhibitors are also being discovered by empirical screening of covalent fragment libraries (Backus et al, 2016;Craven et al, 2018;Johansson et al, 2019;Kathman et al, 2014Kathman et al, , 2015Parker et al, 2017;Resnick et al, 2019) and by covalent virtual screening (Bensinger et al, 2019;Chowdhury et al, 2019;London et al, 2014;Nnadi et al, 2018;Rachman et al, 2019;Scarpino et al, 2018;Shraga et al, 2019;Toledo Warshaviak et al, 2014). While covalent fragment and virtual screening can potentially discover new scaffolds, the binding affinity of primary hits may be relatively low, and often require laborious medicinal chemistry to reach suitable potency.…”
Section: Introductionmentioning
confidence: 99%
“…It allows users to choose between a “pose prediction” (also named “Lead optimization”, from now on referred to as CovDock-PP) [26]) and a “virtual screening” mode (CovDock-VS) [27]. While the former is designed to predict accurate binding modes via more demanding simulations, the latter allows screening of larger libraries [28,29,30,31] by efficiently decreasing the number of steps in the protocol. However, even CovDock-VS has a throughput (≈15 CPU minutes/ligand) not compatible with the size of our virtual compound collection.…”
Section: Resultsmentioning
confidence: 99%
“…For example, small alterations to the binding mode may force a different orientation of the bound electrophile in relation to the nucleophilic amino acid, preventing efficient covalent bond formation with the POI. To circumvent these issues, research groups have developed cysteine‐targeted covalent fragment libraries already employing physiologically compatible electrophiles such as acrylamides, cyanoacrylamides, chloroacetamides, or vinyl sulfones (Figure C).…”
Section: Covalent Fragment‐based Drug Discoverymentioning
confidence: 99%