9d0s
Crystal structure of human Wee1 kinase domain in complex with inhibitor
Structural highlights
FunctionWEE1_HUMAN Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. Publication Abstract from PubMedOptimizing both on-target and off-target potencies is essential for developing effective and selective small-molecule therapeutics. Free energy calculations offer rapid potency predictions, usually within hours and with experimental accuracy and thus enables efficient identification of promising compounds for synthesis, accelerating early-stage drug discovery campaigns. While free energy predictions are routinely applied to individual proteins, here, we present a free energy framework for efficiently achieving kinome-wide selectivity that led to the discovery of selective Wee1 kinase inhibitors. Ligand-based relative binding free energy calculations rapidly identified multiple novel potent chemical scaffolds. Subsequent protein residue mutation free energy calculations that modified the Wee1 gatekeeper residue, significantly reduced their off-target liabilities across the kinome. Thus, with judicious use of this gatekeeper residue selectivity handle, applying this computational strategy streamlined the optimization of both on-target and off-target potencies, offering a roadmap to expedite drug discovery timelines by decreasing unanticipated off-target toxicities. Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study.,Knight JL, Clark AJ, Wang J, Placzek A, Bos PH, Bhat S, Bell JA, Silvergleid S, Yin W, Gray F, Sun S, Akinsanya K, Abel R, Gerasyuto AI Nat Commun. 2025 Aug 26;16(1):7962. doi: 10.1038/s41467-025-62722-w. PMID:40858617[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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