9D0S

Crystal structure of human Wee1 kinase domain in complex with inhibitor

This is a non-PDB format compatible entry.

Summary for 9D0S

• Entry DOI: 10.2210/pdb9d0s/pdb
• Descriptor: Wee1-like protein kinase, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: tyrosine-protein kinase, kinase, transferase, inhibitor, complex, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33479.32

Authors

Bell, J.A. (deposition date: 2024-08-07, release date: 2025-09-10)

Primary citation

Knight, J.L.,Clark, A.J.,Wang, J.,Placzek, A.,Bos, P.H.,Bhat, S.,Bell, J.A.,Silvergleid, S.,Yin, W.,Gray, F.,Sun, S.,Akinsanya, K.,Abel, R.,Gerasyuto, A.I.
Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study.
Nat Commun, 16:7962-7962, 2025

PubMed Abstract: Optimizing 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.

PubMed: 40858617
DOI: 10.1038/s41467-025-62722-w

Experimental method

X-RAY DIFFRACTION (1.64 Å)