Molecular modeling of soluble proteins

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。我们的研究与Alberto Vita教授（意大利Camerino大学）的实验室合作，重点是确定人类CDA的结构-功能关系，并开发选择性CDA抑制剂。 我们最近进行了一个基于结构的虚拟筛选旨在确定新的CDA配体。我们已经在NCI数据库中确定了大约70种可能与CDA结合的化合物，目前正在对分子进行排序。 此外，结合分子建模与定点诱变，我们已经确定了一个氨基酸残基的功能上必不可少的四级结构的酶的形成至关重要，从而进一步了解其活动的分子机制。 Janus激酶。Janus激酶（JAK）是一个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。 我们进行了分子模拟研究，旨在表征JAK的配体识别的分子决定因素。特别地，我们研究了结合JAK 3的构象和立体化学要求。此外，通过对接研究，我们比较了一个有效的抑制剂与JAK 3和JAK 2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。 在与Joseph Neale教授（乔治敦大学生物系）和西里尔Barinka博士（NCI晶体学家）的合作下，我们正在进行一项虚拟筛选，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，从而进一步了解这种酶的可塑性。 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，其作用更有效地作用于哺乳动物蛋白质而不是寄生虫。由于这些原因，在与教授海蒂G。Elmendorf（乔治敦大学生物系），我们正在进行一个虚拟筛选的配体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。我们的策略是基于同源性建模，分子对接和药效团搜索的组合。

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.