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.
| Costanzi, Stefano; Vilar, Santiago; Micozzi, Daniela et al. (2011) Delineation of the molecular mechanisms of nucleoside recognition by cytidine deaminase through virtual screening. ChemMedChem 6:1452-8 |
| Vilar, Santiago; Chakrabarti, Mayukh; Costanzi, Stefano (2010) Prediction of passive blood-brain partitioning: straightforward and effective classification models based on in silico derived physicochemical descriptors. J Mol Graph Model 28:899-903 |
| Micozzi, Daniela; Pucciarelli, Stefania; Carpi, Francesco M et al. (2010) Role of tyrosine 33 residue for the stabilization of the tetrameric structure of human cytidine deaminase. Int J Biol Macromol 47:471-82 |
| Jiang, Jian-kang; Ghoreschi, Kamran; Deflorian, Francesca et al. (2008) Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 51:8012-8 |
