更新于：2024-11-01

DTYMK

更新于：2024-11-01

基本信息

别名

CDC8、deoxythymidylate kinase、dTMP kinase

+ [4]

简介

Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).

关联

项与 DTYMK 相关的药物

TK-666

靶点

DTYMK

作用机制

DTYMK inhibitors

在研机构

AstraZeneca PLC

原研机构

AstraZeneca PLC

在研适应症

革兰氏阳性细菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

TMPK inhibitors(Ghent University)

靶点

DTYMK

作用机制

DTYMK inhibitors

在研机构

Ghent University

原研机构

Ghent University

在研适应症

易感染结核分枝杆菌

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DTYMK 相关的临床结果

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100 项与 DTYMK 相关的转化医学

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0 项与 DTYMK 相关的专利（医药）

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586

项与 DTYMK 相关的文献（医药）

2024-12-31·Journal of Enzyme Inhibition and Medicinal Chemistry

Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPK mt ) inhibition activity and molecular modelling studies

Article

作者: Mahran, Mona A. ; Shehat, Michael G. ; Atta, Amal ; Fahmy, Salwa ; Sriram, Dharmarajan ; Labouta, Ibrahim M. ; El-Shoukrofy, Mai S.

New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H₃₇Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.

2024-10-12·Journal of Biomolecular Structure and Dynamics

In silico design based on quantum chemical, molecular docking studies and ADMET predictions of ciprofloxacin derivatives as novel potential antibacterial and antimycrobacterium agents

Article

作者: Benchouk, Wafaa ; Benselama, Wafa

Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. In this paper, we report the prediction of new ciprofloxacin derivatives by quantum chemical, molecular docking studies and pharmacokinetic properties. Theoretical studies were performed by geometry optimization computation using B3LYP level at 6-311 G (d,p) basis set. The absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters were predicted and the result show that all compounds have a great ADMET profile. To study the antibacterial, anti-Mycobacterium tuberculosis activities, ciprofloxacin and its derivatives were interacted with the proteins: Thymidylate Kinase (PDB: 4QGG), Biotin carboxylase (PDB: 3JZF) and β-lactamase BlaC (PDB: 3N7W). The results of the docking studies indicate that one pharmacophore designed presents a great inhibition behavior against gram-positive organism (4QGG) and significant interactions observed between the compound and ARG48, GLN101, ARG105 and GLU37 residues of 4QGG. Also, another derivative designed present the best inhibition against gram-negative organism (3JZF) several interactions were noticed between the compound and GLY165, ILE287, LEU278, HIS236, HIS209, MET169 and LYS159 residues of (3JZF). As well as, one designed candidate is good inhibitors for β-lactamase (3N7W) multiple no bonded interactions were observed between the compound and SER84, ILE117, ASN186, LYS87, ARG187, ASN186 and THR251 residues of(3N7W). Molecular dynamics (MD) simulation study was also performed for 100 ns to confirm the stability behaviour of the main protein and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders. Natural bonding orbital analysis, reactivity indices and molecular electrostatic potential were carried out. The research finding of this study can be helpful to design a new potent antibacterial, antimycrobacterium candidate's drugs that will serve as the basis for future in vitro and in vivo research.Communicated by Ramaswamy H. Sarma.

2024-08-01·Molecular Diversity

Identification of mycobacterial Thymidylate kinase inhibitors: a comprehensive pharmacophore, machine learning, molecular docking, and molecular dynamics simulation studies

Article

作者: Pawar, Surbhi Pravin ; Dahlous, Kholood A ; Patil, Pritee Chunarkar ; Chikhale, Rupesh V ; Kolpe, Mahima Sudhir ; Bhowmick, Shovonlal ; Mohammad, Saikh ; Shinde, Omkar Dilip

AbstractThymidylate kinase (TMK) is a pivotal enzyme in Mycobacterium tuberculosis (Mtb), crucial for phosphorylating thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), thereby playing a critical role in DNA biosynthesis. Dysregulation or inhibition of TMK activity disrupts DNA replication and cell division, making it an attractive target for anti-tuberculosis drug development. In this study, the statistically validated pharmacophore mode was developed from a set of known TMK inhibitors. Further, the robust pharmacophore was considered for screening the Enamine database. The chemical space was reduced through multiple molecular docking approaches, pharmacokinetics, and absolute binding energy estimation. Two different molecular docking algorithms favor the strong binding affinity of the proposed molecules towards TMK. Machine learning-based absolute binding energy also showed the potentiality of the proposed molecules. The binding interactions analysis exposed the strong binding affinity between the proposed molecules and active site amino residues of TMK. Several statistical parameters from all atoms MD simulation explained the stability between proposed molecules and TMK in the dynamic states. The MM-GBSA approach also found a strong binding affinity for each proposed molecule. Therefore, the proposed molecules might be crucial TMK inhibitors for managing Mtb inhibition subjected to in vitro/in vivo validations.

项与 DTYMK 相关的新闻（医药）

2023-07-24

·药创客

上海交大团队研发水凝胶微球疫苗，增强消融后抗肿瘤免疫反应

点击上方图片链接可报名近日，上海交通大学附属瑞金医院王忠敏、崔文国共同通讯在《Nature Communications》上发表研究论文“Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy”，通过在雄性小鼠的原位胰腺癌模型中的试验表明，水凝胶微球疫苗以安全有效的方式将免疫冷肿瘤微环境转化为热环境，从而显著提高存活率并抑制远处转移瘤的生长。研究结果提示，该团队开发了一种用于消融后免疫疗法的癌症水凝胶微球疫苗。与最近专注于肿瘤内递送外源性抗原或免疫佐剂的工作相反，水凝胶微球疫苗充当一般免疫放大器，触发CD103 CD11b+− cDC1介导的抗原交叉呈递级联的火箭样扩增，导致消融治疗后内源性CD8 T细胞的抗肿瘤免疫力急剧增强。简而言之，我们将Cas9质粒和CD40L分别加载到脂质体和CaCO+3纳米颗粒中，然后将它们与FLT3L细胞因子和透明质酸（HA）混合，以在微流体控制下创建水凝胶微球疫苗。水凝胶微球疫苗诱导cDC1介导的抗原交叉呈递和CD8 T细胞活化的火箭样级联扩增，以安全有效的方式促进胰腺癌从“冷”肿瘤向“热”肿瘤的转化。最后，水凝胶疫苗有效激活全身抗肿瘤免疫，抑制远处转移，提高荷瘤小鼠存活率。将cDC1活化的水凝胶微球疫苗用作一般免疫放大器，在消融治疗后扩增cDC1/CD8 T细胞抗肿瘤轴。总之，水凝胶微球疫苗提供了一种通过促进cDC8介导的免疫级联来有效扩增内源性CD1 T细胞抗肿瘤免疫的策略。与传统的ICB疗法相比，联合策略也可能是未来肿瘤内免疫疗法的新兴趋势。参考资料：https://www.nature.com/articles/s41467-023-39759-w点击上面图片报名识别微信二维码，添加小编，符合条件者即可申请加入微信群！请注明：姓名+研究方向！声明：本文旨在传递更多信息，版权归原作者所有。原创文章转载均需经过授权并注明来源，如涉及内容、版权或其他问题请时联系小编删除！文章仅代表作者个人观点，并不代表公众号立场。本公众号拥有对此声明的最终解释权！投稿邮箱：yck19876@163.com

疫苗免疫疗法