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DUckCov: a Dynamic Undocking‐Based Virtual Screening Protocol for Covalent Binders
Author(s) -
Rachman Moira,
Scarpino Andrea,
Bajusz Dávid,
Pálfy Gyula,
Vida István,
Perczel András,
Barril Xavier,
Keserű György M.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900078
Subject(s) - covalent bond , docking (animal) , chemistry , covalent binding , non covalent interactions , virtual screening , computational biology , computer science , combinatorial chemistry , nanotechnology , molecular dynamics , computational chemistry , materials science , molecule , biology , organic chemistry , medicine , hydrogen bond , nursing
Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non‐conserved nucleophilic residues, optimizing the noncovalent binding framework is important to improve potency and selectivity of covalent binders toward the desired target. Significant efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction. To highlight the value of the noncovalent complex in the covalent binding process, here we describe a new protocol using tethered and constrained docking in combination with Dynamic Undocking (DUck) as a tool to privilege strong protein binders for the identification of novel covalent inhibitors. At the end of the protocol, dedicated covalent docking methods were used to rank and select the virtual hits based on the predicted binding mode. By validating the method on JAK3 and KRas, we demonstrate how this fast iterative protocol can be applied to explore a wide chemical space and identify potent targeted covalent inhibitors.