Recently, targeted covalent kinase inhibitor design has been gaining renewed interest in pharmaceutical industry. Current covalent kinase inhibitor design targets a cysteine next to the ATP-binding pocket; however, cysteines are far away from the druggable sites of many kinases, making the applicability of such strategy rather limited. Inspired by the recent development of lysine-targeting chemical probes, we hypothesized that the current type II inhibitors that target the inactive states of kinases can be modified to covalently link the catalytic lysine for addressing the selectivity and resistance issues. Using a newly developed computational tool -- continuous constant pH molecular dynamics based on the latest Amber force field and generalized Born implicit-solvent model, we scanned the entire human kinome for reactive catalytic lysines. We found that the catalytic lysines of a dozen of different kinases in the αC helix-out and DFG-out conformation are nucleophilic, showing significantly shifted pKa’s down to the physiological pH range. Somewhat surprisingly, covalently targetable lysines as well as cysteines located in other positions were also identified. Our computational tool, which offers accurate and rapidly converging pKa predictions, can be used to scan reactivities of other residues of current interest. As such, the tool has the potential to accelerate the discovery of covalent small molecule drugs for improving the treatment of many diseases.

Computational reactivity scanning for designing lysine targeted covalent kinase inhibitors

2019 Spring National Meeting

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