A5006790855- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cytokine Signaling Pathways and Interactions
- Pharmacogenetics and Drug Metabolism
- Chronic Myeloid Leukemia Treatments
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Acute Myeloid Leukemia Research
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- Neurotransmitter Receptor Influence on Behavior
- Protein Structure and Dynamics
- Schizophrenia research and treatment
- Eicosanoids and Hypertension Pharmacology
- Chemokine receptors and signaling
- Protein Tyrosine Phosphatases
- Glycosylation and Glycoproteins Research
- Enzyme Structure and Function
- Nitric Oxide and Endothelin Effects
- Epigenetics and DNA Methylation
- Synthesis and Biological Activity
- Biochemical and Molecular Research
- Neuroscience and Neuropharmacology Research
- Pancreatic function and diabetes
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
South Australian Health and Medical Research Institute
2022-2024
The University of Adelaide
2022-2024
Flinders University
2014-2024
Flinders Medical Centre
2014-2024
Bedford Hospital
2022
Bedford Hospital NHS Trust
2022
South Australia Pathology
2021
Bioinformatics Institute
2020
Agency for Science, Technology and Research
2020
National University of Singapore
2020
The Automated force field Topology Builder (ATB, http://compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for wide range of molecules appropriate use in molecular simulations, computational drug design, X-ray refinement. ATB has three primary functions: (1) to act as repository have been parametrized part the GROMOS family fields, (2) pre-equilibrated systems starting configurations dynamics simulations (solvent mixtures, lipid adopt...
Molecular dynamics (MD) simulation is an emerging in silico technique with potential applications diverse areas of pharmacology. Over the past three decades MD has evolved as area importance for understanding atomic basis complex phenomena such molecular recognition, protein folding, and transport ions small molecules across membranes. The application simulations isolation conjunction experimental approaches have provided increased structure-function relationships demonstrated promise drug discovery.
The human UDP glycosyltransferase (UGT) superfamily comprises four families of enzymes that catalyze the addition sugar residues to small lipophilic chemicals. UGT1 and UGT2 use UDP-glucuronic acid, UGT3 UDP-N-acetylglucosamine, UDP-glucose, UDP-xylose conjugate xenobiotics, including drugs endobiotics such as metabolic byproducts, hormones, signaling molecules. This metabolism renders substrate more polar readily excreted from body and/or functionally inactive. fourth UGT family, called...
Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, question whether second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis,...
The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. more accurate and also computationally demanding techniques are the so-called methods which use conformational sampling from molecular dynamics or Monte Carlo simulations generate thermodynamic averages. Two such widely applied integration (TI) recently introduced enveloping distribution (EDS) In both cases energies through alchemical perturbations of one ligand...
Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D2-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative cognitive impairments. For the last few decades, discovery efforts sought nondopaminergic compounds with aim to effectively treat broad schizophrenia. In this viewpoint, we provide an overview trace-amine...
Drugs and other chemicals frequently bind nonspecifically to the constituents of an in vitro incubation mixture, particularly enzyme source [e.g., human liver microsomes (HLM)]. Correction for nonspecific binding (NSB) is essential accurate calculation kinetic parameters <i>K</i><sub>m</sub>, <i>Cl</i><sub>int</sub>, <i>K</i><sub>i</sub>. Many tyrosine kinase inhibitors (TKIs) are lipophilic organic bases that nonionized at physiologic pH. Attempts measure NSB several TKIs HLM by equilibrium...
Although there is evidence for an important role of UGT2B10 in the N-glucuronidation drugs and other xenobiotics, inhibitor selectivity this enzyme poorly understood. This study sought primarily to characterize inhibition by UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors used reaction phenotyping, 34 antidepressant antipsychotic that contain amine functional group. Initial studies demonstrated cotinine a highly selective substrate human liver microsomal UGT2B10. The kinetics...
ADME genes are a group of that involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In study, our comprehensive analyses pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral for 21 different types. Most also showed high interindividual variability cancer-specific cohorts. Using Kaplan-Meier...
Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding nature potency CYP17A1 inhibition abiraterone. Here, we establish that is a slow-, tight-binding inhibitor CYP17A1, with initial weak binding preceding subsequent slow isomerization to high-affinity CYP17A1-abiraterone complex. The constant final complex...
Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit Gram-positive and Gram-negative bacteria. Many crystal structures ribosomes with oxazolidinone ligands have been reported in literature, facilitating structure-based design using methods such as molecular docking. It would be great interest know advance how well docking can reproduce correct ligand binding modes rank these correctly. We examined performance five programs (AutoDock 4,...
The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind alternate subsites within a given binding pocket leading cooperative when linked. In this study, the human phenylethanolamine N-methyltransferase used illustrate how (a) current protocols may fail detect cooperatively, (b) theoretical approaches can be validate potential hits, and (c) apparent false positives obtained screening against cocktails in fact indicate promising leads.
Arginine analogues incorporating carboxylate bioisosteric functional groups exhibit low micromolar inhibitory potential against human dimethylarginine dimethylaminohydrolase (DDAH), a key enzyme in the nitric oxide pathway.
Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery JAK2 V617F mutation present patients with myeloproliferative neoplasms (MPN); however, structural basis oncogenicity has only recently elucidated. New studies reveal a role for other domains, beyond domain, that contribute to pathogenic signaling. Here we evaluate structure-based approaches led recently-approved type I (fedratinib and pacritinib), as well II (BBT594 CHZ868) pseudokinase under...
Abstract Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants (SNV) have been found in patients with schizophrenia and metabolic disorders. However, frequency geographically diverse populations functional effects such are unknown. In this study, we aimed to characterise distribution SNVs five different WHO regions using Database Genotypes Phenotypes (dbGaP)...