Global disease burden due to age related cognitive decline and dementias, especially Alzheimer’s disease, are a growing public health problem. Current treatments fail to completely prevent or cure dementia. A target of interest is the Insulin Regulated Aminopeptidase (IRAP) enzyme, inhibitors of IRAP have shown promise in preventing and reversing neurological degeneration associated with dementia. Structural information about IRAP when bound to an inhibitor is lacking, however, and future ligand design depends on knowledge of the mechanism of inhibition. We used long term MD simulations of IRAP bound to various ligands to investigate the conformational changes undergone by IRAP. PCA analysis was also used to investigate larger changes in the enzyme. A highly stable pose for a known spiro-oxindole inhibitor was found with key interactions between the ligand and SER546 and TYR 954, providing useful data for the design of future inhibitors of the IRAP enzyme.

Psilocybin is a hallucinogenic compound found in fungi and is currently evaluated inclinical trials for treatment of depression, anxiety and addiction. Psilocybin is aprodrug of the pharmacologically active metabolite, psilocin. The synthetic route topsilocybin relies on synthesizing psilocin from the starting material, 4-hydroxyindoleand latter converting psilocin into psilocybin by phosphorylation. The synthesis ofpsilocybin has been challenging because of the labile nature of the phosphorylationdibenzyl ester reagent and related intermediates. Several attempts to optimizepsilocybin synthesis have been published but there is still a need for furtherimprovements.The first aim of this project was to synthesize psilocybin using literature methods,while the second aim was to optimize the phosphorylation step with differentreagents and conditions.Initial studies focused on coupling the two-side chain carbon onto position three ofthe indole, this required protection of the hydroxyl group which was achieved byacylation in room temperature. With sufficient amount of dimethylamine solution, theamine addition reaction was investigated and resulted in a pure product. Thefollowing reduction with lithium aluminum hydride provided an unknown side-productinstead of psilocin.The first aim was successfully accomplished, up to psilocin, with pure intermediatesbut low yields. The second aim was not achieved due to lack of time and access tothe laboratory during covid-19 crisis. However, a literature survey of reagents andconditions for phosphorylation was performed which enables continuation of theproject.

No description available.

No description available.

Adenosine receptors (ARs) are a family belonging to the GPCR superfamily, involved with multiple physiological processes and widely distributed throughout the body. In this study, we focus on the A3 AR due to its vast scale applications in various pathophysiological conditions such as inflammation, pain, allergic asthma, and cancer chemotherapy. We report the validation of the binding mode of A3 AR antagonists, through a comprehensive in-silico mutagenesis study using free energy perturbations, reproducing prior experimental site-directed mutagenesis data for A3 AR antagonists. After validating the antagonist binding mode, we performed an extensive in-silico site-directed mutagenesis study on the hA3 AR using potent, selective, and structurally simple A3 AR antagonist based on the N-(2,6-diarylpyrimidin-4- yl)acetamide scaffold (pyrimidine core). The results of this study will be used to design in- vitro site-directed mutagenesis performed by collaborators (University of Barcelona). Once the binding mode of this scaffold is validated, it will be the basis for the design of compounds with two well-defined functionalities: a fluorophore moiety and bivalent ligands that target A3 dimers. The discovery of novel mutations on the hA3 AR is a step forward in the development of both chemically simple, potent, and selective A3 AR antagonists as well as in the characterization and crystallization of the A3 AR.

No description available.

No description available.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Medicinal Chemistry." Includes bibliographical references (p. 198-218).

Thesis (Ph. D.)--Rutgers University, 2010. / "Graduate Program in Medicinal Chemistry." Includes bibliographical references.

Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along with a NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples, as well as if there is a significant difference in these two kits at varying concentrations of apixaban. Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along withused witha NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples,as well as and to evaluate if there is a significant difference in these two kits at varying concentrations of apixaban.