9D0S の概要
| エントリーDOI | 10.2210/pdb9d0s/pdb |
| 分子名称 | Wee1-like protein kinase, SODIUM ION, CHLORIDE ION, ... (5 entities in total) |
| 機能のキーワード | tyrosine-protein kinase, kinase, transferase, inhibitor, complex, transferase-inhibitor complex, transferase/inhibitor |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 33479.32 |
| 構造登録者 | |
| 主引用文献 | 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 Cited by 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: 40858617DOI: 10.1038/s41467-025-62722-w 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.64 Å) |
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