Molecular modeling of soluble proteins

可溶性蛋白质的分子建模

• 批准号: 7967154
• 负责人: Stefano Costanzi
• 金额: $ 7.52万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967154
• 关键词: Actins; Amino Acids; Antiviral Agents; Binding; Biological; Biology; Blood - brain barrier anatomy; Brain; Collaborations; Complex; Computer Assisted; Cytidine; Cytidine Deaminase; Cytidine Deaminase Inhibitor; Databases; Deamination; Development; Docking; Enzymes; Family; G-Protein-Coupled Receptors; Giardia; Giardia lamblia; Glutamate Carboxypeptidase II; Glutamates; Homology Modeling; Human; Hydrolysis; Interferons; Italy; JAK2 gene; JAK3 gene; Janus kinase; Laboratories; Ligands; Malignant neoplasm of prostate; Molecular; Molecular Models; Molecular Weight; N-acetylaspartate; N-acetylaspartylglutamate; Parasites; Process; Protein Tyrosine Kinase; Proteins; Research; Screening procedure; Signal Transduction; Site-Directed Mutagenesis; Stroke; Structure; Structure-Activity Relationship; Toxin; Universities; Uridine; base; computer studies; cytokine; drug discovery; enzyme structure; inhibitor/antagonist; macromolecule; molecular modeling; nervous system disorder; novel; novel therapeutics; pharmacophore; prevent; professor; virtual

Human cytidine deaminase. Cytidine deaminase (CDA) is a cytosolic enzyme which catalyzes the hydrolytic deamination of cytidine to uridine. CDA causes the degradation of several cytidine based compounds potentially active as anticancer or antiviral agents. Our research, in collaboration with the laboratory of Prof. Alberto Vita (University of Camerino, Italy) focuses on the determination of the structure-function relationships of the human CDA and on the development of selective CDA inhibitors. We have recently conducted a structure-based virtual screening intended to identify novel CDA ligands. We have identified about seventy compounds in the NCI database that could potentially bind to CDA and are currently in the process of ordering the molecules. Moreover, combining molecular modeling with site-directed mutagenesis we have identified an amino acid residue crucial for the formation of the functionally essential quaternary structure of the enzyme, thus furthering the understanding of the moelcular mechanism underlying its activity. Janus kinases. Janus kinases (JAKs) are a family of four cytoplasmic tyrosine kinases involved in signaling by various cytokines and interferons. We conducted molecular modeling studies aimed at the characterization of the molecular determinants of ligand recognition by JAKs. In particular, we studied the conformational and stereochemical requirement for binding to JAK3. Furthermore, by means of docking studies, we compared the complexes of a potent inhibitor with JAK3 and JAK2. Glutamate carboxypeptidase II. Glutamate carboxypeptidase II (GCPII) is an enzyme that catalyzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to N-acetylaspartate and glutamate. Its inhibitors have the potential of being applied to the treatment of prostate cancer or brain stroke, depending on their ability of crossing the blood-brain barrier. In collaboration with Prof. Joseph Neale (Department of Biology, Georgetown University) and Dr. Cyril Barinka (crystallographer at the NCI) we are conducting a virtual screening intended to identify novel GCPII inhibitors capable to cross the blood brain barrier, to be used in the treatment of neurological diseases. The discovery of structural diverse ligands would also allow us to solve new crystal structures, thus furthering our understanding of the plasticity of this enzyme. Giardia lamblia actin. Inhibitors of Giardia lamblia actin have the potential of providing a novel therapeutic strategy to prevent the attachment of this parasite to the host. However, most currently known actin inhibitors are natural toxins that act more potently at the mammalian proteins rather than at the parasite. For these reasons, in collaboration with professor Heidi G. Elmendorf (Department of Biology, Georgetown University) we are conducting a virtual screening for ligands capable of selectively perturbing the attachment of Giardia actin without interfering with the human protein. Our strategy is based on a combination of homology modeling, molecular docking, and pharmacophore searches.

人胞苷脱氨酶。胞苷脱氨酶（CDA）是一种胞质酶，催化胞苷水解脱氨基为尿苷。 CDA 会导致几种具有潜在抗癌或抗病毒活性的胞苷基化合物的降解。我们与 Alberto Vita 教授（意大利卡梅里诺大学）实验室合作进行的研究重点是确定人类 CDA 的结构与功能关系以及选择性 CDA 抑制剂的开发。 我们最近进行了基于结构的虚拟筛选，旨在鉴定新型 CDA 配体。我们已经在 NCI 数据库中鉴定出大约 70 种可能与 CDA 结合的化合物，目前正在订购这些分子。 此外，将分子建模与定点诱变相结合，我们已经确定了对于酶的功能必需的四级结构的形成至关重要的氨基酸残基，从而进一步了解其活性背后的分子机制。 Janus 激酶。 Janus 激酶 (JAK) 是由四种细胞质酪氨酸激酶组成的家族，参与各种细胞因子和干扰素的信号传导。 我们进行了分子建模研究，旨在表征 JAK 配体识别的分子决定因素。特别是，我们研究了与 JAK3 结合的构象和立体化学要求。此外，通过对接研究，我们比较了有效抑制剂与 JAK3 和 JAK2 的复合物。 谷氨酸羧肽酶 II。谷氨酸羧肽酶 II (GCPII) 是一种催化 N-乙酰天冬氨酰谷氨酸 (NAAG) 水解为 N-乙酰天冬氨酸和谷氨酸的酶。其抑制剂有可能应用于治疗前列腺癌或脑中风，具体取决于它们穿越血脑屏障的能力。 我们与 Joseph Neale 教授（乔治城大学生物学系）和 Cyril Barinka 博士（NCI 晶体学家）合作进行虚拟筛选，旨在鉴定能够穿过血脑屏障的新型 GCPII 抑制剂，用于治疗神经系统疾病。结构多样的配体的发现也将使我们能够解决新的晶体结构，从而进一步加深我们对这种酶的可塑性的理解。 贾第鞭毛虫肌动蛋白。 贾第鞭毛虫肌动蛋白抑制剂有可能提供一种新的治疗策略来防止这种寄生虫附着在宿主身上。然而，目前已知的大多数肌动蛋白抑制剂是天然毒素，其对哺乳动物蛋白质的作用比对寄生虫的作用更有效。出于这些原因，我们与 Heidi G. Elmendorf 教授（乔治城大学生物学系）合作，对能够选择性干扰贾第鞭毛虫肌动蛋白附着而不干扰人类蛋白质的配体进行虚拟筛选。我们的策略基于同源建模、分子对接和药效团搜索的组合。