蛋白激酶Wee1在双链DNA破裂引发的G2/M细胞周期检查点激活中起着至关重要的作用。通过在Tyr15残基上磷酸化并因此使与Cdk1/Cdc2连接的cyclin B失活，它完成了这个任务，从而导致G2细胞周期停滞和DNA损伤后的有丝分裂延迟。尽管有所进展，目前只有Wee1抑制剂MK1775进入到了Ⅱ期临床试验，这为小分子发现的创新化学结构开发提出了挑战。为了应对这一挑战，我们采用了MK1775-WEE1复合物（PDB ID：5V5Y）的电子药效团模型，利用FDA批准的药物的体外筛选。我们根据对接得分、关键残基相互作用和配体占有率选择了六种药物进行类似物创造。利用“DrugSpaceX”数据库，我们通过专家定义的转化生成了2776个类似物。我们的研究发现，DE90612是排名第一的类似物，其次是DE363106、DE489678、DE395383、DE90548、DE689343、DE395019和DE538066。这些类似物引入了其他数据库中没有发现的独特结构。t-SNE结构多样性分布图揭示了与替莫唑胺（Temozolomide）相关的有望进行WEE1抑制剂开发的有希望的转化。对WEE1-DE90612复合物（替莫唑胺类似物）进行了200纳秒的模拟，结果表明其稳定性良好，DE90612与活性位点残基形成牢固的键合，并且在ASN376和CYS379处保持重要的接触。这些结果突出了DE90612在WEE1结合位点的潜在抑制性质，为其抗癌活性的进一步体外和体内研究提供了有利依据。我们的研究方法为创造具有适当生物性质的多样化WEE1抑制剂，以用于潜在的肿瘤学治疗提供了有前景的途径。由Ramaswamy H. Sarma传达。

The protein kinase Wee1 plays a vital role in the G2/M cell cycle checkpoint activation, triggered by double-stranded DNA disruptions. It fulfills this task by phosphorylating and consequently deactivating the cyclin B linked to Cdk1/Cdc2 at the Tyr15 residue, leading to a G2 cell cycle halt and subsequent delay of mitosis post DNA damage. Despite advancements, only the Wee1 inhibitor MK1775 has made it to Phase II clinical trials, presenting a challenge in innovative chemical structure development for small molecule discovery. To navigate this challenge, we employed an e-pharmacophore model of the MK1775-WEE1 complex (PDB ID: 5V5Y), using in silico screening of FDA-approved drugs. We chose six drugs for analog creation, guided by docking scores, key residue interactions, and ligand occupancy. Utilizing the 'DrugSpaceX' database, we generated 2,776 analogues via expert-defined transformations. Our findings identified DE90612 as the top-ranked analogue, followed by DE363106, DE489678, DE395383, DE90548, DE689343, DE395019, and DE538066. These analogues introduced unique structures not found in other databases. A t-SNE structurally diversified distribution map unveiled promising transformations linked to Temozolomide for WEE1 inhibitor development. Simulations of the WEE1-DE90612 complex (a Temozolomide analogue) for 200 nanoseconds demonstrated stability, with DE90612 forging robust bonds with active site residues and sustaining vital contacts at ASN376 and CYS379. These results underscore DE90612's potential inhibitory properties at the WEE1 binding site, warranting additional in vitro and in vivo exploration for its anticancer activity. Our approach outlines a promising pathway for creating diverse WEE1 inhibitors with suitable biological properties for potential oncology therapeutics.Communicated by Ramaswamy H. Sarma.