Molecular modeling of soluble proteins

可溶性蛋白质的分子建模

• 批准号: 8148674
• 负责人: Stefano Costanzi
• 金额: $ 13.35万
• 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/8148674
• 关键词: Molecular Models; Proteins; molecular modeling

In the course of this fiscal year, we have worked on the soluble systems described in the following paragraphs, which constitute attractive targets for the development of pharmaceutical agents. 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. 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. 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 of the currently known actin inhibitors are natural toxins that act more potently at the mammalian proteins rather than at the parasite, while, for a pharmaceutical application, the opposite would be required. In particular, during this fiscal year, we have conducted the research and accomplished the results described in the following paragraphs. 1) Developed a computational model for the prediction of passive blood-brain partitioning. We developed this model in order to select, among the potential GCPII inhibitors suggested by a virtual screening that we conducted last year, those that are more likely to access the brain. Notably, however, this effective model can be generally applied to the study of any organic compound and drug candidate. 2) Continued our virtual screening efforts for the identification of 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. Experimental collaborators: Prof. Joseph Neale (Department of Biology, Georgetown University) 3) Completed a virtual screening for the identification of CDA inhibitors and identified several active compounds. Experimental collaborators: Prof. Alberto Vita (University of Camerino, Italy). 4) Rationalized the role of a specific amino acid residue (Tyr 33) in the stabilization of the CDA quaternary structure, through the combination of molecular modeling and biochemical experiments. Experimental collaborators: Prof. Alberto Vita (University of Camerino, Italy). 5) Continued the studies on the structure-function relationships of CDA. Experimental collaborators: Prof. Alberto Vita (University of Camerino, Italy). 6) Studied similarities and differences between human and Giardia actin. The insights generated from this study will be fundamental for our search for compounds capable of selectively perturbing the attachment of Giardia actin without interfering with the human protein.

在本财政年度期间，我们致力于以下段落所述的可溶性系统，这些系统构成了药物开发的诱人目标。 人胞苷脱氨酶。胞苷脱氨酶（CDA）是一种胞质酶，催化胞苷水解脱氨为尿苷。CDA导致几种基于胞苷的化合物的降解，这些化合物可能具有抗癌或抗病毒剂的活性。 谷氨酸羧肽酶II。谷氨酸羧肽酶II（GCPII）是一种催化N-乙酰乙酰基谷氨酸（NAAG）水解为N-乙酰天冬氨酸和谷氨酸的酶。它的抑制剂具有应用于治疗前列腺癌或脑卒中的潜力，这取决于它们穿过血脑屏障的能力。 蓝氏贾第鞭毛虫肌动蛋白蓝氏贾第鞭毛虫肌动蛋白的抑制剂有可能提供一种新的治疗策略，以防止这种寄生虫附着到主机。然而，大多数目前已知的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强，而对于药物应用，则需要相反的作用。 特别是在本财政年度，我们进行了研究，并取得了以下段落所述的成果。 1)开发了一个计算模型，用于预测被动血脑分配。我们开发了这个模型，以便在我们去年进行的虚拟筛选中选择潜在的GCPII抑制剂，这些抑制剂更有可能进入大脑。然而，值得注意的是，这种有效的模型通常可以应用于任何有机化合物和候选药物的研究。 2)继续我们的虚拟筛选工作，以识别能够穿过血脑屏障的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，从而进一步了解这种酶的可塑性。 实验合作者：Joseph Neale教授（乔治敦大学生物系） 3)完成了CDA抑制剂鉴定的虚拟筛选，并鉴定了几种活性化合物。实验合作者：Alberto Vita教授（卡梅里诺大学，意大利）。 4)通过分子模拟和生物化学实验相结合，证实了一个特定的氨基酸残基（Tyr 33）在CDA四级结构稳定中的作用。实验合作者：Alberto Vita教授（卡梅里诺大学，意大利）。 5)继续对CDA的构效关系进行研究。实验合作者：Alberto Vita教授（卡梅里诺大学，意大利）。 6)研究了人类和贾第虫肌动蛋白的异同。从这项研究中产生的见解将是我们寻找能够选择性地干扰贾第虫肌动蛋白的附着而不干扰人类蛋白质的化合物的基础。