Chemicals and Drugs Commons^™

Abstraction Of Dimensional Relevance Of Molecular Representation: Generation Of Novel Inhibitors Against Malarial Plasmodium Falciparum Plasmepsin Iv, Christopher B. Abdul-Wahid

Undergraduate Honors Theses

The malarial parasite Plasmodium falciparum is endemic to 50% of the world's population, killing three million people a year, many of whom are children under five years of age. Due in part to the development of malarial resistance to current drug therapies, novel drug targets are being sought. The malarial hemolytic aspartic protease Plasmepsins are such targets of rational drug design.

We are developing a methodology to rapidly generate combinatorial libraries of chemical structures using a one-dimensional representation (Simplified molecular input line entry specification (SMILES)) of a molecule, to automatically generate a minimized three-dimensional representation (SYBYLMOL2), and to screen this …

Protein Pyrophosphorylation By Inositol Pyrophosphates Is A Posttranslational Event, Rashna Bhandari, Adolfo Saiardi, Yousef Ahmadibeni, Adele M. Snowman, Adam C. Resnick, Troels Z. Kristiansen, Henrik Molina, Akhilesh Pandey, J. Kent Werner Jr., Krishna R. Juluri, Yong Xu, Glenn D. Prestwich, Keykavous Parang, Solomon H. Snyder

Pharmacy Faculty Articles and Research

In a previous study, we showed that the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP(7)) physiologically phosphorylates mammalian and yeast proteins. We now report that this phosphate transfer reflects pyrophosphorylation. Thus, proteins must be prephosphorylated by ATIP to prime them for IP(7) phosphorylation. IP(7) phosphorylates synthetic phosphopeptides but not if their phosphates have been masked by methylation or pyrophosphorylation. Moreover, IP(7) phosphorylated peptides are more acid-labile and more resistant to phosphatases than ATIP phosphorylated peptides, indicating a different type of phosphate bond. Pyrophosphorylation may represent a novel mode of signaling to proteins.

Synthesis And Antifungal Properties Of Alpha-Methoxy And Alpha-Hydroxyl Substituted 4-Thiatetradecanoic Acids, Nestor Carballeira, Rosann O'Neill, Keykavous Parang

Pharmacy Faculty Articles and Research

4-Thiatetradecanoic acid exhibited weak antifungal activities against Candida albicans (ATCC 60193), Cryptococcus neoformans (ATCC 6603 1), and Aspergillus niger (ATCC 16404) (MIC = 4.8-12.7 mM). It has been demonstrated that alpha-methoxylation efficiently blocks P-oxidation and significantly improve the antifungal activities of fatty acids. We examined whether antifungal activity of 4-thiatetradecanoic acid can be improved by a-substitution. The unprecedented (+/-)-2-tiydroxy-4-thiatetradecanoic acid was synthesized in four steps (20% overall yield), while the (+/-)-2-methoxy-4-thiatetradecanoic acid was synthesized in five steps (14% overall yield) starting from 1-decanethiol. The key step in the synthesis was the hydrolysis of a trimethylsilyloxynitrile. In general, the novel (+/-)-2-methoxy-4-thiatetradecanoic …

Coupling Coherence Distinguishes Structure Sensitivity In Protein Electron Transfer, Tatiana Prytkova, Igor V. Kurnikov, David Beratan

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Quantum mechanical analysis of electron tunneling in nine thermally fluctuating cytochrome b562 derivatives reveals two distinct protein-mediated coupling limits. A structure-insensitive regime arises for redox partners coupled through dynamically averaged multiple-coupling pathways (in seven of the nine derivatives) where heme-edge coupling leads to the multiple-pathway regime. A structure-dependent limit governs redox partners coupled through a dominant pathway (in two of the nine derivatives) where axial-ligand coupling generates the single-pathway limit and slower rates. This two-regime paradigm provides a unified description of electron transfer rates in 26 ruthenium-modified heme and blue-copper proteins, as well as in numerous photosynthetic proteins.

The Endogenous Cannabinoid Anandamide Inhibits Cromakalim-Activated K+ Currents In Follicle-Enclosed Xenopus Oocytes, Murat Oz, Keun-Hang Susan Yang, Meral Dinc, Toni S. Shippenberg

Mathematics, Physics, and Computer Science Faculty Articles and Research

The effect of the endogenous cannabinoid anandamide on K+ currents activated by the ATP-sensitive potassium (KATP) channel opener cromakalim was investigated in follicle-enclosed Xenopus oocytes using the two-electrode voltage-clamp technique. Anandamide (1–90 μM) reversibly inhibited cromakalim-induced K+ currents, with an IC50 value of 8.1 ± 2 μM. Inhibition was noncompetitive and independent of membrane potential. Coapplication of anandamide with the cannabinoid type 1 (CB1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) (1 μM), the CB2 receptor antagonist N-[(1S)endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) (1 μM), or pertussis toxin (5 μg/ml) did not alter the inhibitory effect of anandamide, suggesting that known cannabinoid receptors …

Knowledge And Beliefs Of Adolescents Regarding Sexually Transmitted Infections And Hiv/Aids In A Rural District In Pakistan, Hafsa Raheel, Franklin White, Muhammad Masood Kadir, Zafar Fatmi

Community Health Sciences

Objective:

To assess the knowledge and beliefs of adolescents (15-19 years girls and boys) regarding sexually transmitted infections (STIs) and HIV/AIDS.

Methods:

A community based cross-sectional survey was conducted in October 2002 in a rural district (Mirpurkhas) of Sindh province, Pakistan.

Results:

A total of 428 adolescent girls and boys were interviewed. Only 44% correctly named at least one STI, while 55% knew at least two modes of transmission for HIV/AIDS. Adolescents with education greater than or equal to secondary level, those who were able to read the newspaper, possessed electricity in their homes and were allowed to meet their …

Flavin Charge Transfer Transitions Assist Dna Photolyase Electron Transfer, Spiros S. Skourtis, Tatiana Prytkova, David Beratan

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

This contribution describes molecular dynamics, semi-empirical and ab-initio studies of the primary photo-induced electron transfer reaction in DNA photolyase. DNA photolyases are FADH−-containing proteins that repair UV-damaged DNA by photo-induced electron transfer. A DNA photolyase recognizes and binds to cyclobutatne pyrimidine dimer lesions of DNA. The protein repairs a bound lesion by transferring an electron to the lesion from FADH−, upon photo-excitation of FADH− with 350–450 nm light. We compute the lowest singlet excited states of FADH− in DNA photolyase using INDO/S configuration interaction, time-dependent density-functional, and time-dependent Hartree-Fock methods. The calculations identify the lowest singlet excited state of FADH− …

Interactions Of Mtfabh With Its Substrates And Inhibitors Reveal Novel Mechanistic Insights, Sarbjot Singh Sachdeva

Theses and Dissertations

Tuberculosis emerged from its grave to be one of the deadliest diseases of the present time after recently developing a synergy with AIDS. A fatty acid condensing enzyme-mtFabH has been proposed to connect the key processes involved in biosynthesis of mycolic acids, an important component of mycobacterial cell wall. It condenses long acyl Coenzymes A (CoA; up to C20CoA) with malonyl Acyl Carrier Protein (ACP) to form the elongated β-ketoacyl-ACP which further undergoes rounds of elongation to form mero-mycolate branch of mature mycolic acids. Owing to its proposed central position in mycolic acid synthesis, mtFabH has attracted considerable attention as …

On The Binding Of N1-Substituted Tryptamines At H5-Ht6 Receptors, Abner Nyamwaro Nyandege

Theses and Dissertations

Serotonin was first discovered in the late 1940s as a vasotonic factor and is now considered a principal neurotransmitter in the nervous system. 5-HT6 receptors are one of the most recently identified members of the serotonin receptor family which consists of seven classes (5-HT1-5-HT7). 5-HT6 receptors are G-protein coupled, positively coupled to an adenylate cyclase second messenger system and are primarily found in the central nervous system (CNS). The exact functional role of 5-HT6 receptors has not been determined, but is implicated to have possible involvement in certain neuropsychiatric disorders and cognition. To investigate the functional role of these receptors, …

Outcomes Of Peginterferon Alfa-2a And Ribavirin Combination Therapy In A Resident-Initiated, Multidisciplinary, Hepatitis C Clinic, Nicole M. Agostino Do, Erini Vasiliadis Do, K Nadeem Ahmed Md, Suzanne J. Templer Do, Edward R. Norris Md, Fapa, Fapm, Charles M. Brooks Md, Eric J. Gertner Md, Mph, Joseph L. Yozviak Do, Facp

Department of Medicine

No abstract provided.

Does Hiv-1 Affect Sensitivity To Addictive Drugs? Methamphetamine-Induced Conditioned Place Preference In Hiv-1 Transgenic Rats, Brent Foster Costleigh

Seton Hall University Dissertations and Theses (ETDs)

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Dna Multiplex Hybridization On Microarrays And Thermodynamic Stability In Solution: A Direct Comparison, Daniel J. Fish, M. Todd Horne, Greg P. Brewood, Jim P. Goodarzi, Saba Alemayehu, Ashwini Bhandiwad, Robert P. Searles, Albert S. Benight

Chemistry Faculty Publications and Presentations

Hybridization intensities of 30 distinct short duplex DNAs measured on spotted microarrays, were directly compared with thermodynamic stabilities measured in solution. DNA sequences were designed to promote formation of perfect match, or hybrid duplexes containing tandem mismatches. Thermodynamic parameters DeltaH degrees , DeltaS degrees and DeltaG degrees of melting transitions in solution were evaluated directly using differential scanning calorimetry. Quantitative comparison with results from 63 multiplex microarray hybridization experiments provided a linear relationship for perfect match and most mismatch duplexes. Examination of outliers suggests that both duplex length and relative position of tandem mismatches could be important factors contributing to …

The Occipital And Sacral Pressures Experienced By Healthy Volunteers Under Spinal Immobilization: A Trial Of Three Surfaces, Ruairí De Fréin, Fintan Sheerin

Articles

The development of a pressure ulcer is of great significance to the life-long rehabilitative management of the person with a spinal cord injury, and may indeed delay and repeatedly interfere with that process. That the period preceding admission to the specialized spinal injury unit is crucial with regard to pressure ulcer development is evident in the professional literature. Both anecdotal and empirical evidence indicates that a significant number of pressure ulcers occur as a result of management provided prior to admission, and that such ulcers are more likely to occur in those patients who have undergone a transfer process from …

Novel Sulfated 4-Hydroxycinnamic Acid Oligomers As Potent Anticoagulants, Brian Lawrence Henry

Theses and Dissertations

The occurrence of thrombosis in several pathophysiological conditions creates a huge need for anticoagulation therapy. Thrombin and factor Xa have been prime targets for regulation of clotting through the direct and indirect mechanism of inhibition. This work investigates chemo-enzymatically prepared oligomers of 4-hydroxycinnamic acids (DHPs) as potential anticoagulants. Oligomers were prepared through peroxidase-catalyzed oxidative coupling of 4-hydroxycinnamic acids. The products resulting from this reaction are called CDs, FDs and SDs. Structurally, these sulfated DHPs are unique and do not resemble any of the anticoagulants known in the literature.DHP oligomers were found to increase clotting times at concentrations comparable to heparin. …