更新于：2024-11-01

CDK2

更新于：2024-11-01

基本信息

别名

CDK2、CDKN2、Cell division protein kinase 2

+ [4]

简介

Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).

关联

121

项与 CDK2 相关的药物

Culmerciclib

库莫西利

靶点

CDK2 x CDK4 x CDK6

作用机制

CDK2抑制剂 [+2]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段申请上市

首次获批国家/地区-

首次获批日期1800-01-20

Sapacitabine

沙帕他滨

靶点

CDK2 x CDK9

作用机制

CDK2抑制剂 [+1]

在研机构

Cyclacel Pharmaceuticals, Inc. [+2]

原研机构

Daiichi Sankyo Co., Ltd.

在研适应症

急性髓性白血病 [+1]

非在研适应症

晚期恶性实体瘤 [+8]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

Zotiraciclib

靶点

CDK2 x CDK5 x CDK7 x CDK9 x FLT3 x JAK2

作用机制

CDK2抑制剂 [+5]

在研机构

北京智康博药肿瘤医学研究有限公司 [+2]

原研机构

杏国新药股份有限公司

在研适应症

高级别胶质瘤 [+1]

非在研适应症

急性淋巴细胞白血病 [+9]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

126

项与 CDK2 相关的临床试验

NCT06662773 / Not yet recruiting临床1期

Phase I Clinical Trial Evaluating Drug Drug Interactions of TQB3616 Capsules

To evaluate the effect of itraconazole/rifampicin on the pharmacokinetics of TQB3616 capsules.
To assess the safety of a single dose of oral TQB3616 capsules and in combination with itraconazole/rifampicin.

开始日期2024-11-01

申办/合作机构

正大天晴药业集团股份有限公司

NCT06586957 / Recruiting临床1期

A Phase 1, First-in-human, Open-label Study to Evaluate the Safety, Tolerability, PK, and Preliminary Anti-tumor Activity of the Novel Oral CDK2 Degrader NKT3964 in Adults With Advanced/Metastatic Solid Tumors

The goal of the Dose Escalation phase of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity to determine the preliminary recommended dose for expansion (RDE) of NKT3964 in adults with advanced or metastatic solid tumors. The goal of the Expansion phase of the study is to evaluate the preliminary anti-tumor activity of NKT3964 at the RDEs based on objective response rate (ORR) and determine the preliminary recommended Phase 2 dose (RP2D).

开始日期2024-09-19

申办/合作机构

NiKang Therapeutics, Inc.初创企业

CTR20241278 / Active, not recruiting临床1期

评估健康成年受试者多次给药TQB3616胶囊安全性、耐受性的I期临床试验.

评估健康成年受试者多次给药TQB3616胶囊后的安全性、耐受性。评估健康成年受试者多次给药TQB3616胶囊后的药代动力学。

开始日期2024-06-11

申办/合作机构

正大天晴药业集团股份有限公司

[+1]

100 项与 CDK2 相关的临床结果

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100 项与 CDK2 相关的转化医学

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0 项与 CDK2 相关的专利（医药）

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8,945

项与 CDK2 相关的文献（医药）

2025-02-01·Combinatorial Chemistry & High Throughput Screening

Network Pharmacology and Experimental Validation to Elucidate the Pharmacological Mechanisms of Luteolin Against Chondrocyte Senescence

Article

作者: Zhou, Faxin ; Luo, Hao ; Long, Ling ; Cao, Kai ; Xiong, Jiachao ; Lv, Hao ; Gu, Jiaxiang ; Wang, Yi ; Lin, Sijian ; Tang, Xiaokai

Background:Luteolin, a flavonoid found in various medicinal plants, has shown promising antioxidant, anti-inflammatory, and anti-aging properties. The cartilaginous endplate (CEP) represents a crucial constituent of the intervertebral disc (IVD), assuming a pivotal responsibility in upholding both the structural and functional stability of the IVD.Objective:Exploring the precise mechanism underlying the protective effects of luteolin against senescence and degeneration of endplate chondrocytes (EPCs).Methods:Relevant targets associated with luteolin and aging were obtained from publicly available databases. To ascertain cellular functions and signaling pathways, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed. Core genes were identified through the construction of a protein-protein interaction (PPI) network. Molecular docking (MD) was utilized to assess the binding affinity of luteolin to these core genes. Finally, the impact of luteolin on the senescence and degeneration of EPCs was evaluated in an in vitro cellular senescence model induced by tert-butyl hydroperoxide (TBHP).Results:There are 145 overlapping targets between luteolin and senescence. Analysis using GO revealed that these targets primarily participate in cellular response to oxidative stress and reactive oxygen species. KEGG analysis demonstrated that these markers mainly associate with signaling pathways such as p53 and PI3K-Akt. MD simulations exhibited luteolin’s binding affinity to P53, Cyclin-dependent kinase (CDK)2, and CDK4. Cell cycle, cell proliferation, and β- galactosidase assays confirmed that luteolin mitigated senescence in SW1353 cells. Western blot assays exhibited that luteolin significantly suppressed the expression of Matrix Metallopeptidase (MMP) 13, P53, and P21, while concurrently promoting CDK2, CDK4, and Collagen Type II Alpha 1 (COL2A1) expression.Conclusion:In summary, luteolin demonstrated beneficial properties against aging and degeneration in EPCs, offering novel insights to mitigate the progression of intervertebral disc degeneration (IVDD).

2025-01-01·Journal of Ethnopharmacology

Dehydrocorydaline attenuates myocardial ischemia-reperfusion injury via the FoXO signalling pathway: A multimodal study based on network pharmacology, molecular docking, and experimental study

Article

作者: Chen, Keji ; Chen, Daxin ; Meizhu, Wu ; Yu, Zikai ; Shen, Aling ; Renfeng, Li ; Li, Mengfan ; Zhi, Guo ; Hua, Qu ; Zucheng, Shang ; Zikai, Yu ; Guo, Zhi ; Yang, Wenwen ; Qu, Hua ; Li, Hongzheng ; Daxin, Chen ; Aling, Shen ; Hongzheng, Li ; Lu, Yingdong ; Li, Renfeng ; Wenwen, Yang ; Changgeng, Fu ; Lin, Guosheng ; Shang, Zucheng ; Keji, Chen ; Yingdong, Lu ; Mengfan, Li ; Fu, Changgeng ; Guosheng, Lin ; Wu, Meizhu

ETHNOPHARMACOLOGICAL RELEVANCEDehydrocorydaline (DHC), an active component of Corydalis yanhusuo (Y.H. Chou & Chun C. Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu (Papaveraceae), exhibits protective and pain-relieving effects on coronary heart disease, but the underlying mechanism still remains unknown.AIM OF THE STUDYNetwork pharmacology and experimental validation both in vivo and in vitro were applied to assess whether DHC can treat myocardial ischemia-reperfusion injury (MIRI) by regulating the forkhead box O (FoxO) signalling pathway to inhibit apoptosis.MATERIALS AND METHODSDHC and MIRI targets were retrieved from various databases. Molecular docking and microscale thermophoresis (MST) determined potential binding affinity. An in vivo mouse model of MIRI was established by ligating the left anterior descending coronary artery. C57BL/6N mice were divided into sham, MIRI, and DHC (intraperitoneal injection of 5 mg/kg DHC) groups. Haematoxylin and eosin, Masson, and immunohistochemical stainings verified DHC treatment effects and the involved signalling pathways. In vitro, H9c2 cells were incubated with DHC and underwent hypoxia/reoxygenation. TUNEL, JC-1, and reactive oxygen species stainings and western blots were used to explore the protective effects of DHC and the underlying mechanisms.RESULTSVenny analysis identified 120 common targets from 121 DHC and 23,354 MIRI targets. DHC exhibited high affinity for CCND1, CDK2, and MDM2 (<-7 kcal/mol). In vivo, DHC attenuated decreases in left ventricular ejection fraction and fractional shortening, reduced infarct sizes, and decreased cTnI and lactate dehydrogenase levels. In vitro, DHC alleviated apoptosis and oxidative stress in the hypoxia/reoxygenation model by attenuating ΔΨm disruption; reducing the production of reactive oxygen species; upregulating Bax and CCND1 via the FoxO signalling pathway, as well as cleaved-caspase 8; downregulating the apoptosis-associated proteins Bcl-2, Bid, cleaved-caspase 3, and cleaved-caspase 9; and promoting the phosphorylation of FOXO1A and MDM2.CONCLUSIONBy upregulating the FoxO signaling pathway to inhibit apoptosis, DHC exerts a cardioprotective effect, which could serve as a potential therapeutic option for MIRI.

2024-12-31·Redox Report

Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways

Article

作者: Hou, Wen-Shuang ; Tang, Yan-Jun ; Wang, Chang ; Li, Shu-Mei ; Wang, An-Qi ; Cao, Jing-Long ; Jin, Cheng-Hao ; Liu, Jian

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.

458

项与 CDK2 相关的新闻（医药）

2024-10-31

·药精通Bio

22.5亿美元！诺华青睐的VAV1分子胶长啥样？市场前景如何？

IND2025主会场授课已被预定，大会第一天下午茶歇前授课时间段预定开始，咨询热线：177 0186 0390。点击图片，查看IND2024会后报告资讯 2024 年 10 月 28 日，Monte Rosa Therapeutics宣布了一项全球独家开发和与诺华公司签订商业化许可协议，以推进 VAV1 MGD，包括 MRT-6160。MRT-6160 目前正在进行针对免疫介导疾病的 1 期单次递增剂量 (SAD)/多次递增剂量 (MAD) 健康志愿者研究。根据协议条款，诺华将获得 MRT-6160 和其他 VAV1 MGD 的开发、制造和商业化的全球独家权利，并将负责从 2 期临床研究开始的所有临床开发和商业化。Monte Rosa 仍负责完成正在进行的 MRT-6160 1 期临床研究。 MRT-6160 是一种有效的、高选择性的、口服生物可利用的研究性 VAV1 降解剂，VAV1 是 T 细胞和 B 细胞受体下游的关键信号蛋白。临床前研究表明，VAV1 深度降解，导致与免疫介导病症相关的细胞因子显著减少，而对其他蛋白质没有可检测到的影响。MRT-6160 在多种免疫介导疾病的临床前模型中显示出有希望的活性。根据协议条款，诺华同意向 Monte Rosa 预付 1.5 亿美元。从第二阶段研究开始，Monte Rosa 有资格获得高达 21 亿美元的开发、监管和销售里程碑，以及美国以外净销售额的分级特许权使用费。Monte Rosa 将共同资助任何 3 期临床开发，并将分享与 MRT-6160 在美国制造和商业化相关的任何利润和损失。目前MRT-6160的I期SAD/MAD研究正在进行中，临床数据预计于2025年第1季度获得。关于VAV1分子胶的相关背景信息本公众号早有介绍【研发前沿|分子胶的理性设计(2)——CDK2分子胶与Monte Rosa的野望】、【分子胶的理性设计(3)：Monte Rosa教你如何“调教”CRBN】，今年的分子胶行业总结报告中，也对此简要介绍过。不过一直未曾对此做过详尽报道，这里做个总结与补充。关于VAV1的生物学背景早在今年8月，Monte Rosa在Trends in Immunology上发文报道了VAV1的相关生物学背景（DOI: 10.1016/j.it.2024.06.004），表明转录因子VAV 1作为一种“undruggable”蛋白，是原代人CD4+和CD8+T细胞中T细胞受体（TCR）活化和细胞因子产生的关键正调节剂;数据表明VAV1的丧失/抑制调节自身免疫和炎症;以及来自T和T/B细胞介导的关节炎和结肠炎疾病模型的有希望的临床前数据，显示通过蛋白质降解的选择性VAV1靶向的有效性。 VAV 1在抗原受体信号转导中扮演着关键角色 VAV 1的核心鸟嘌呤核苷酸交换因子（GEF）依赖性功能 VAV1 是经多次验证的T细胞和B细胞受体下游的关键支架蛋白和信号分子。VAV1敲除能阻断T细胞介导的B细胞活性(IL-17A, IL-17F, IL-6, IL-2, TNF, sIgG)。 VAV1分子胶的商业价值近年来靶向治疗的出现为自身免疫性疾病和慢性炎症性疾病的治疗带来了突破，例如像炎症性肠病、类风湿性关节炎、脊柱关节炎和银屑病等，但仍存在着许多未满足的临床需求。目前，针对自身免疫性疾病和慢性炎症性疾病的治疗策略主要包括生物制剂和口服小分子药物，然而，治疗失败、药物耐受性差、对糖皮质激素依赖以及缺乏针对某些疾病的靶向治疗等问题仍未得到解决。现有的治疗方案，例如生物制剂，在治疗某些疾病方面疗效显著，但它们通常为注射剂，且存在免疫原性等问题。而口服小分子药物尽管易于给药，但由于其靶点通常位于细胞内，限制了其作用范围。此外，现有的靶向治疗药物往往仅能抑制单一蛋白或信号通路，疗效并不理想。因此，研发更多针对自身免疫性疾病和慢性炎症性疾病的新型药物，尤其是那些能够靶向多个重要信号通路，并具有安全性和有效性的药物，依然是未来研究的重要方向。相比于上述疗法存在的缺陷，VAV1分子胶的优势主要体现在以下几个方面：靶向性强: VAV1 主要表达在造血细胞中，包括 T 细胞和 B 细胞，因此针对 VAV1 的分子胶可以更有效地抑制免疫反应，减少对其他器官和组织的损伤。多重作用机制: VAV1 作为一种双功能蛋白，同时具有 GEF 活性和支架蛋白功能。VAV1 分子胶通过降解 VAV1 蛋白，可以同时抑制其 GEF 活性和支架蛋白功能，从而阻断 T 细胞和 B 细胞的多种重要信号通路，更全面地抑制免疫反应。有效性高: 已有研究表明，VAV1 分子胶在多种自身免疫性疾病动物模型中展现出良好的治疗效果，例如在关节炎和结肠炎模型中，VAV1 分子胶能够显著减轻炎症反应，改善组织损伤。总之，VAV1 分子胶作为一种新型的靶向治疗药物，具有靶向性强、多重作用机制和有效性高三大优势，有望成为治疗自身免疫性疾病和慢性炎症性疾病的新希望。 Monte Rosa也在文章中列出了现有自免疗法的相关机制与药物发展态势，VAV1分子胶具有独特的机制，具有广泛的潜在应用潜力，可通过安全的口服治疗解决多种自身免疫性疾病。实验研究也表明了VAV1分子胶对于T细胞介导的B细胞活化具有更选择性且更为高效的阻断活性。至于VAV1体内药效： MRT-6160改善T细胞转移诱导的结肠炎优于标准疗法。 MRT-6160减少溃疡性结肠炎T细胞转移模型中炎症介导的结肠损伤和细胞因子产生 MRT-6160抑制风湿性关节炎疾病模型中的疾病进展、关节炎症和自身抗体产生，同样优于标准疗法 MRT-6160在T细胞介导的多发性硬化自身免疫疾病模型中引发剂量依赖性活性 Monte Rosa因此对这个项目具有很高的期望，认为其是多种自身免疫性疾病的口服替代疗法，有望对目前千亿美元的自免药物市场带来强有力的冲击。 MRT-6160长啥样到了最关键的环节，Monte Rosa的VAV1分子胶MRT-6160的具体结构长啥样？其实结合公开Poster信息与专利（WO2024151547A1），很容易便能猜到。首先是MRT-6160的降解活性：DC50 = 7 nM，Dmax = 97%。专利中是什么情况呢？这里偷懒借用之前报告中的内容，显而易见了，通过活性数据，简单的SAR分析，以及成药性判断，Cpd.185，极大概率便是MRT-6160的具体结构。后话此前也提到过，VAV1是与GSPT1的G-loop表面高度相似性的靶点。VAV1分子胶的发现依赖于Monte Rosa的QUEEN平台，基于AI+结构生物学所开发的，是真正的AIDD药物。更惊人的是大善人在GitHub上对这个项目做了开源，感兴趣的可以拿来跑一下，助力发现新的VAV1分子胶。第一次关注VAV1分子胶始于去年7月份，长久以来看好的项目终于通过诺华的这笔交易得到了初步证实，还是很让人欣慰的。期待将来的临床结果进一步证实这一点。 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 OTC2024类器官前沿应用与3D细胞培养论坛圆满落幕，点击图片可查看会后报告，咨询OTC2025类器官论坛请联系：王晨 180 1628 8769

临床3期临床1期临床2期临床申请细胞疗法

2024-10-28

·BioPharmaDive

Monte Rosa joins with Novartis in ‘molecular glue’ drug deal

Dive Brief:Novartis will pay $150 million to gain rights to molecular glue degraders being developed by biotechnology company Monte Rosa Therapeutics to target an immune signaling protein, known as VAV1, that has long been considered undruggable.The deal, announced by the companies Monday morning, could yield up to $2.1 billion in further payments by Novartis to Monte Rosa should the licensed research reach certain development, regulatory and sales milestones.Molecular glue degraders are small molecule drugs that join together a target protein with an enzyme responsible for flagging cellular detritus for disposal. In Monte Rosas case, the company believes degrading VAV1 could weaken certain immune cell functions, thereby slowing the progression of immune-mediated diseases.Dive Insight:Novartis deal with Monte Rosa centers on an early-stage drug candidate dubbed MRT-6160 thats currently in a Phase 1 study of healthy volunteers.Monte Rosa and Novartis see potential for MRT-6160 to treat multiple systemic and neurological autoimmune diseases, Monte Rosa CEO Markus Warmuth said in an email to BioPharma Dive.Under the deal, Monte Rosa will wrap up the ongoing Phase 1 clinical study, while Novartis will handle development from Phase 2 onwards. The biotech will co-fund any Phase 3 testing that occurs and also share in any profits or losses associated with MRT-6160s commercialization, should it get that far.“Novartis has had a long-standing interest in molecular glue degraders, which offer the potential to tackle challenging biological targets, said Fiona Marshall, head of biomedical research at Novartis, in the companies statement. We are excited about their application in immunology and the early progress we have seen by Monte Rosa in this space and with MRT-6160.For Monte Rosa, Novartis support will help it fully explore the potential of MRT-6160 in a variety of immune diseases, Warmuth said in his email. The company plans to use the $150 million it will receive from Novartis to extend its operating runway and advance its own research.In addition to VAV1, Monte Rosa is exploring targeting other proteins, including ones called NEK7, CDK2 and CCNE1, with its molecular glue technology.Monte Rosa previously partnered with Novartis cross-town rival Roche to apply molecular glue degraders to cancer and neurological diseases. Other biotechs are exploring the drug concept as well, and have struck collaborations with Pfizer, Astellas and Bristol Myers Squibb. '

临床1期蛋白降解靶向嵌合体

2024-10-26

·精准药物

【Chemical Science】浙江大学侯廷军等：基于片段的分子生成模型FragGen

基于三维结构的分子生成是生成式人工智能在药物发现中的成功应用之一。早期出现的基于原子的分子生成模型如LiGAN、Pkt2Mol、DiffBP和ResGen等，输出的分子通常具有较好的对接分数，但同时也普遍存在两个问题：一是生成的分子构象经常出现扭曲或偏离口袋（图-1 GraphBP和DiffBP）；二是倾向于生成大的并环结构来填充口袋（图-1PktMol和ResGen）。虽然这样的结构可能会与靶蛋白产生更强的相互作用，但是复杂的结构往往不利于合成且易导致毒性。基于片段的分子生成以可合成的分子片段为基础，为提高生成分子的可合成性提供了方向，但是现有的基于片段的分子生成模型如FLAG，在生成具有合理几何形状的分子方面表现不佳（图-1）。因此，在基于结构的药物设计中，迫切需要一种可靠的基于片段的分子生成模型。浙江大学侯廷军课题组联合中国科学技术大学和蒙特利尔学习算法研究所在Chemical Science上发表文章“FragGen: Towards 3D Geometry Reliable Fragment-based Molecular Generation[1]”。基于现有分子生成方法的优缺点，作者提出了一种组合策略并基于该策略开发了基于片段的分子生成方法FragGen，该方法显著提高了生成分子的结构质量和可合成性，克服了以前模型的主要局限性。FragGen已经成功地应用于现实场景并在nM水平上设计了II型激酶抑制剂。图-1 不同方法生成的分子部分列举。为解决生成分子几何结构不合理的问题，作者总结了目前在分子生成领域常用的六种几何结构处理方法（图-2）：1）内部坐标法，在预测键长、键角和二面角之前先确定所有原子的连接顺序，但基于复杂的蛋白质口袋环境生成合理的拓扑顺序是困难的，且该方法主要关注局部的原子连接信息，忽视了分子整体的空间结构和对称性。2）笛卡尔坐标法，通过对三维坐标进行概率学习来预测原子坐标，由于没有考虑原子间的局部化学结构约束，每次预测误差的累积会导致最终几何结构不合理。3）相对矢量法，通过预测原子间的坐标向量差将自由度限制在键长上，减少需要预测的信息量，降低预测误差对整体分子几何结构的影响。4）GeomGNN，利用等变图神经网络学习原子之间的力并用于更新原子坐标，不仅训练和推理过程简单直接且能够高效生成符合全局几何特性的分子，但在实现局部几何结构的准确性方面仍存在局限性。5）GeomOPT，通过模拟分子内部的力场相互作用来预测原子的位置，理论上可以避免生成局部结构不合理的分子模型，但是为了找到合理的分子结构需要进行大量的迭代计算，在优化过程中还有可能陷入局部能量最小值，从而导致最终分子构象的扭曲。6）距离几何法，通过模拟原子间的距离来避免神经网络设计中的等变性需求，减少了模型构建的复杂性，但自由度过剩使得无法从距离矩阵中确定唯一的三维坐标，因此常导致构象扭曲。图-2 不同几何处理方法的工作流程、面临的挑战、应用举例和其他模型信息（MG：分子生成，S-MG：基于结构的分子生成，CG：构象生成和S-CG：基于结构的构象生成，即分子对接）。基于以上各种方法的优缺点，作者提出了一种用于基于片段的分子生成的组合策略（图-3）：首先通过相互作用学习模块分析蛋白质口袋中的几何特征和关键位点，从片段库中挑选合适的初始片段并将其放在口袋合适的位置，接着利用相对矢量法检测潜在子口袋以确定后续片段组装的合适位置，然后预测下一个片段的类型并使用GeomOPT通过力场优化方法调整片段之间的键长、键角和相对位置，确保连接部分的几何结构合理性，同时结合化学知识如杂化轨道理论对生成的分子碎片进行初始化以保证其遵循化学规则，最后使用vonMises损失函数预测分子片段之间的二面角，确保二面角的旋转符合分子整体的几何约束，并使生成的分子片段能在三维空间中合理排布。图-3 FragGen生成分子的工作流程。作者引入了两个新的指标来定量评估生成分子的几何合理性：松弛能量（RelaxE）和优化均方根偏差（OptRMSD）。即计算对生成分子进行力场优化后释放的能量（图-4A）和RMSD。由于大的芳香族体系不易产生构象变化，因此OptRMSD在多环化合物中的值一般较小，因此ResGen与FragGen生成化合物的OptRMSD值虽然相似，但FragGen生成化合物释放的能量却更低（图-4B-D），展现了其在生成合理几何构象方面的优势。对于FLAG这种易生成扭曲构象的模型，在两个指标上的结果均不理想（图-4B）。图-4 （A）生成和优化后分子几何形状在能量景观图中的位置；（B-D）三种方法中三个例子的RelaxE和OptRMSD值。作者评估和比较了FragGen和其他分子生成方法在CrossDock基准测试集上的性能，结果表明FragGen在VinaScore上的表现优于其他所有方法，在可合成性方面，当其他方法的SA值还在0.3到0.6范围内波动时，FragGen的SA值已经稳定在0.7以上。为证明FragGen在现实场景中的适用性，作者评估了该方法在几个经过充分研究的药物靶标上的性能。结果表明FragGen生成分子与Active数据集（实验验证的化合物）中分子的VinaScore分布较为接近（图-5A），且在VinaScore相似的情况下，FragGen在生成可合成性较好的分子方面的表现远优于ResGen（图-5B）。图-5 （A）FragGen和FLAG在AKT1、CDK2和JAK2三个靶点上生成分子的结合能力（VinaScore）分布；（B）对比可视化前5个分子与靶标的结合能力和可合成性。最后，参考PDGFRβ靶点基于I型抑制剂信息设计II型抑制剂的思路，作者使用FragGen设计了激酶LTK的II型抑制剂并进行了湿实验验证。首先基于间变性淋巴瘤激酶ALK建立LTKDFG-out同源模型，接着将已报道的ALKI型抑制剂对接到LTK模型中并提取与I型口袋核心区域有紧密相互作用的分子片段，然后基于该分子片段进行分子生成。在10分钟内，FragGen生成了97种分子，以氢键供体数< 5，氢键受体数< 10，2 < LogP < 5和可旋转键数< 10为条件过滤后获得10个分子，根据可合成性选择其中的三个进行了湿实验验证分析。其中化合物Darma-1具有最好的活性，IC50值为75.1nM（图-6A）。对结合模式的分析表明Darma-1与LTK的II型口袋形成了全面的物理相互作用（图-6B-D），包括与ASP-155、LYS-35和GLU-52形成的氢键相互作用和其他疏水相互作用。这表明FragGen能够生成在三维空间中形状和排列合理且能够与蛋白质活性位点正确结合的分子结构。图-6 （A）FragGen设计的三个化合物的结构及其对Ba/F3-CLIP1-LTK细胞的抑制活性（IC50）；（B）Darma-1结合构象；（C）三维蛋白-配体相互作用分析；（D）二维蛋白-配体相互作用分析（绿色表示疏水相互作用，蓝色表示氢键相互作用）。小结：作为一种基于片段的分子生成方法，FragGen生成的分子不仅在结合亲合力方面与目前最优的方法表现相当，而且在可合成性方面也表现出较大的优势，对II型LTK抑制剂的成功设计表明了FragGen在实际应用中的潜力。但是FragGen的几何处理策略较为复杂，在复杂体系中进行多次迭代优化时，可能需要大量计算资源，这在应用于大规模片段库筛选时可能会成为瓶颈。此外FragGen在其他靶点上的应用仍需进一步验证。参考文献： [1] Yu, M.; Zeng, Y.; Wang, M.; Hua, C.; Cui, S.; Pan, P.; Hsieh, C.-Y.; Hou, T.; Zhang, O.; Huang, Y.; Chen, S.; Zhang, X.; Lin, H.; Wu, Z.; Zhao, H.; Zhang, Z.; Kang, Y. FragGen: Towards 3D Geometry Reliable Fragment-based Molecular Generation. Chem. Sci. 2024 Oct 16. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓