A5027985101- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Inflammatory mediators and NSAID effects
- Computational Drug Discovery Methods
- vaccines and immunoinformatics approaches
- Insect Resistance and Genetics
- X-ray Diffraction in Crystallography
- Protein Hydrolysis and Bioactive Peptides
- Lipoproteins and Cardiovascular Health
- Crystallography and molecular interactions
- Malaria Research and Control
- Crystallization and Solubility Studies
- Cancer therapeutics and mechanisms
- Synthesis of β-Lactam Compounds
- Renin-Angiotensin System Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Antiplatelet Therapy and Cardiovascular Diseases
- Trypanosoma species research and implications
- Biochemical and Structural Characterization
- Receptor Mechanisms and Signaling
- Click Chemistry and Applications
- Mosquito-borne diseases and control
- Protease and Inhibitor Mechanisms
- Neurobiology and Insect Physiology Research
University College Dublin
2011-2016
Royal College of Surgeons in Ireland
2005-2016
University of Cape Town
1997-2005
Ludwig-Maximilians-Universität München
1999-2001
Harvard University
1999
Association for Language Learning
1920
Columbia University
1920
Harvard University Press
1920
University of Pennsylvania
1920
Bethlehem Area School District
1920
A major cause of the paucity new starting points for drug discovery is lack interaction between academia and industry. Much global resource in biology present universities, whereas focus medicinal chemistry still largely within Open source discovery, with sharing information, clearly a first step towards overcoming this gap. But interface could especially be bridged through scale-up open physical compounds, which would accelerate finding discovery. The Medicines Malaria Venture Box...
We introduce CycloPs, software for the generation of virtual libraries constrained peptides including natural and nonnatural commercially available amino acids. The is written in cross-platform Python programming language, features include generating one-dimensional SMILES three-dimensional SDF formats, suitable screening. stand-alone capable filtering using empirical measurements, peptide synthesizability by standard synthesis techniques, stability, druglike properties peptide. accompanying...
Abstract Background We examined, through genome‐wide association studies ( GWAS ), the correlation between recipient genetic variation and renal function at five yr. Methods Our cohort contained 326 I rish, first time, kidney‐only, deceased donor, transplant recipients on calcineurin inhibitors (263 had a functioning graft yr) 1993 2002. Outcomes were creatinine yr long‐term function. Results Two variants identified showing borderline significance – one chromosome 18 (p = 4.048e‐08,...
The discovery of novel antigens is an essential requirement in devising new diagnostics or vaccines for use control programmes against human tuberculosis (TB) and bovine (bTB). Identification potential epitopes recognised by CD4 + T cells requires prediction peptide binding to MHC class-II, obligatory prerequisite cell recognition. To comprehensively prioritise MHC-II-binding from Mycobacterium bovis , the agent bTB zoonotic TB humans, we integrated three methods with M. proteome using a...
Antimalarial chemotherapy continues to be challenging in view of the emergence drug resistance, especially artemisinin resistance Southeast Asia. It is critical that novel antimalarial drugs are identified inhibit new targets with unexplored mechanisms action. has been demonstrated immunosuppressive rapamycin, which currently clinical use prevent organ-transplant rejection, effects. The Plasmodium falciparum target protein PfFKBP35, a unique immunophilin FK506-binding (FKBP). This family...
Angiotensin-converting enzyme (ACE) is one of a growing number integral membrane proteins that shed from the cell surface through proteolytic cleavage by secretase. To investigate requirements for ectodomain shedding, we replaced glycosylphosphatidylinositol addition sequence in dipeptidase (MDP) - protein not with juxtamembrane stalk, transmembrane (TM) and cytosolic domains ACE. The resulting construct, MDP–STMACE, was targeted to glycosylated enzymically active form, into medium. site...
The role of juxtamembrane stalk glycosylation in modulating cleavage and shedding membrane proteins remains unresolved, despite reports that expressed glycosylation-deficient cells undergo accelerated proteolysis. We have constructed mutants angiotensin-converting enzyme (ACE), a type I ectoprotein is vigorously shed when Chinese hamster ovary cells. Surprisingly, did not significantly inhibit release. Introduction an N-linked glycan directly adjacent to the native site resulted 13-residue,...
Angiotensin-converting enzyme (ACE) is a membrane-anchored ectoprotein that proteolytically cleaved, yielding an enzymatically active soluble ACE. Two mouse monoclonal antibodies, MAbs 1B3 and 5C8, were generated to the C-terminal part of human MAb recognized catalytically ACE, as revealed by ELISA precipitation assays, whereas Western blotting immunohistochemisty on paraffin- embedded sections using 5C8 detected denatured showed extensive cross-reactivity, recognizing 15 species out 16...
We present a plausible productive conformation obtained by docking calculations for the binding of prostaglandin G2 (PGG2) to peroxidase site endoperoxide H synthase-1 (PGHS-1, COX-1). The enzyme−substrate complex stability was verified molecular dynamics. Structural analysis reveals requirements recognition and binding: PGG2 15-hydroperoxide group is in proximity heme iron participates hydrogen bond network with conserved His207 Gln203 water molecule, whereas carboxylate forms salt bridges...
Angiotensin-converting enzyme (ACE) exists as two isoforms: somatic ACE (sACE), comprised of homologous N and C domains, testis (tACE), the domain only. The domains are both active, but show differences in substrate inhibitor specificity. While isoforms shed from cell surface via a sheddase-mediated cleavage, tACE is much more efficiently than sACE. To delineate regions that important catalytic activity, intracellular processing, regulated ectodomain shedding, sequence were replaced with...
The synthetic feasibility of any compound library used for virtual screening is critical to the drug discovery process. TIN, a recursive acronym 'TIN Is Not commercial', combinatorial database enumeration diversity-orientated multicomponent syntheses (MCR). Using 'one-pot' technique, 12 unique small molecule scaffolds were developed, predominantly styrylisoxazoles and bis-acetylenic ketones, with extensive derivatization potential. Importantly, accessible in single operation from...
Proteins secreted by Mycobacterium tuberculosis may play a key role in virulence and also constitute antigens that elicit the host immune response. However, M. protein export machinery has not been characterized. A library of H37Rv genomic DNA fragments ligated into signal sequence selection vector contained leaderless β-lactamase gene an upstream Tac promoter was constructed. Transformation Escherichia coli with on plates containing 50-100 μg ampicillin ml -1 resulted identification 15 Amp...
The purpose of this study was to investigate the blood stage malaria causing parasite, Plasmodium falciparum, predict potential protein interactions between parasite merozoite and host erythrocyte design peptides that could interrupt these predicted interactions. We screened P. falciparum human proteomes for computationally short linear motifs (SLiMs) in cytoplasmic portions transmembrane proteins play roles invasion by merozoite, an essential step malarial pathogenesis. tested thirteen...
Shedding of the ectodomain angiotensin-converting enzyme (ACE) and numerous other membrane-anchored proteins results from a specific cleavage in juxtamembrane (JM) stalk, catalyzed by "sheddases" that are commonly activated phorbol esters inhibited peptide hydroxamates such as TAPI. Sheddases require stalk minimum length steric accessibility. However, we recently found substitution ACE with an epidermal growth factor (EGF)-like domain low-density lipoprotein receptor (LDL-R) did not abolish...
Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray mass spectrometry also yielded large output datasets possible target proteins/genes. However, challenge remains to identify new targets for drug discovery from this wealth information. Further analysis includes and/or molecular biology tools validate findings. This is time consuming expensive, could fail yield novel drugs if protein purification...
Specialized proteases, referred to as sheddases, secretases, or membrane-protein-solubilizing proteases (MPSPs), solubilize the extracellular domains of diverse membrane proteins by catalyzing a specific cleavage in juxtamembrane stalk regions such proteins. A representative MPSP (tumor necrosis factor-alpha convertase) was cloned recently and shown be disintegrin metalloprotease that is inhibited peptide hydroxamates including compound TAPI. Substrate determinants specify MPSPs remain...
Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They thus unable to inhibit free-radical induced tissue injury associated with PGHS activity, which can occur independently COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found have significant PGHS-POX inhibitory (IC50 = 72 µM). To define critical parameters for inhibition,...