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.
Highlights
A covalent binder first requires the formation of an initial noncovalent complex with its target, followed by the chemical reaction between the ligand’s electrophilic warhead and the nucleophilic residue
The performance gap in terms of binding mode prediction among the different covalent docking programs was shown to vary significantly depending on various factors.[23]
Because the majority of kinase inhibitors bind to the highly conserved hinge motif, DUckCov application on JAK3 was focused on the identification of covalent ligands displaying strong interactions at this region
Summary
The TCI approach has proven to be a valuable tool in targeting protein binding sites, which were previously considered as undruggable, as well as to combat drug resistance by targeting poorly conserved non-catalytic residues. The performance gap in terms of binding mode prediction among the different covalent docking programs was shown to vary significantly depending on various factors (i.e., protein target, accessibility of the nucleophilic residue, amount of noncovalent interactions occurring in the complex).[23] On the other hand, the speed of the simulation remains one of the main bottlenecks that can drastically affect the size and diversity of the covalent libraries used for screening applications To this end, we present DUckCov, a time-efficient multistep VS protocol for the identification of novel covalent binders. The protocol was prospectively validated in two case studies: a target with highly conserved noncovalent interactions (JAK3) and another one where the noncovalent interactions are not conserved across known inhibitors (KRasG12C)
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