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DUckCov: a Dynamic Undocking‐Based Virtual Screening Protocol for Covalent Binders

Rachman, Moira and Scarpino, Andrea and Bajusz, Dávid and Pálfy, Gyula and Vida, István and Perczel, András and Barril, Xavier and Keserű, György Miklós (2019) DUckCov: a Dynamic Undocking‐Based Virtual Screening Protocol for Covalent Binders. CHEMMEDCHEM, 14 (10). pp. 1011-1021. ISSN 1860-7179

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Abstract

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.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia
Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
Depositing User: Dóra K. Menyhárd
Date Deposited: 21 Nov 2019 09:53
Last Modified: 21 Nov 2019 09:53
URI: http://real.mtak.hu/id/eprint/103468

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