ORCID Profile
0000-0002-6900-3862
Current Organisation
RMIT University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 05-1997
DOI: 10.1111/J.1440-1681.1997.TB01204.X
Abstract: 1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was > or = 160 mmHg systolic or > or = 90 mmHg diastolic if systolic BP was > or = 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82,000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP > or = 160/90 mmHg. Forty-seven per cent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.
Publisher: American Chemical Society (ACS)
Date: 14-09-2021
DOI: 10.26434/CHEMRXIV-2021-56DS7
Abstract: Accurate methods to predict the free energies of protein-ligand interactions have great potential to assist rational drug design. In this work, we used molecular dynamics simulations with alchemical perturbation to predict the binding of carbohydrate-based ligands to influenza virus neuraminidase (N2). This specific drug target is a challenging test system for alchemical free energy methods because it has flexible binding site motifs. We use a molecular dynamics protocol that works for longer time scales than are often reported in previous molecular dynamics studies of N2. We demonstrated that N2-ligand complex stability and that accurate N2 150-loop dynamics, on a 350 ns time scale, are both force field-dependent (AMBER99SB-ILDN, GAFF and TIP4P water are required). Further, we showed that crystallographic waters must be retained to maintain stability of N2-ligand complexes over 350 ns. Using our modelling protocol, we were able to determine relative binding free energy values between neuraminidase ligands which correlated strongly with experimental differences in pIC50 values (R = -0.96, ρ = 0.86, N = 13, sig 0.0001). It is anticipated that the molecular dynamics protocol and the relative binding free energy methods reported here, will both be useful in expediting the discovery of novel therapeutics for N2 and other homologous glycohydrolases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1996
DOI: 10.1161/01.STR.27.11.2020
Abstract: Background and Purpose Given that hypertension is now relatively well controlled and use of antiplatelet agents has increased, our primary aims were to investigate the risk of intracerebral hemorrhage (ICH) associated with hypertension and use of antiplatelet agents. Methods In this city-wide case-control study, 370 consecutive cases of primary ICH, verified by CT or autopsy, were identified from one of 13 Melbourne hospitals. Ten subjects (or their next of kin) could not be located and 29 refused to participate, resulting in 331 eventual cases. Patients were aged between 18 and 80 years and had no prior stroke. Population-based control subjects were in idually age- (±5 years), sex-, and geographically matched to subject cases. A questionnaire administered to participants (or next of kin) elicited information about prior exposure to various potential risk factors. Results Hypertension approximately doubled the risk of ICH (odds ratio, 2.55 95% confidence interval, 1.72 to 3.79). The use of aspirinlike drugs, in doses used for secondary prevention of ischemic stroke or cardiac disease, was not associated with an increased risk of ICH (odds ratio, 0.66 95% confidence interval, 0.20 to 2.21). Factors associated with a reduced risk of ICH were a history of cardiovascular disease, arthritis, or high cholesterol level being moderately overweight or using hormone replacement therapy and drinking coffee. Conclusions Hypertension was the most important risk factor for ICH but not as high as previously reported, nor was it higher than that reported for ischemic stroke. There was no evidence for any association between the use of aspirinlike drugs and ICH.
Publisher: American Chemical Society (ACS)
Date: 04-08-2017
DOI: 10.1021/ACS.JMEDCHEM.7B00681
Abstract: Underpinning all drug discovery projects is the interaction between a drug and its target, usually a protein. Thus, improved methods for predicting the magnitude of protein-ligand interactions have the potential to improve the efficiency of drug development. In this review, we describe the principles of free energy methods used for the calculation of protein-ligand binding free energies, the challenges associated with these methods, and recent advances developed to address these difficulties. We then present case studies from 2005 to 2017, each demonstrating that alchemical free energy methods can assist rational drug design projects. We conclude that alchemical methods are becoming a feasible reality in medicinal chemistry research due to improved computational resources and algorithms and that alchemical free energy predictions methods are close to becoming a mainstream tool for medicinal chemists.
Publisher: BMJ
Date: 05-08-1995
Abstract: To assess the efficacy and safety of a repeat course of treatment with transdermal nicotine for cessation of smoking in a brief intervention setting. Randomised, double blind, placebo controlled trial with follow up for 26 weeks. 629 smokers who had unsuccessfully attempted to stop smoking by using active transdermal nicotine and brief behavioural counselling. Smokers were motivated to quit smoking for a second time and smoked > or = 15 cigarettes a day. Twelve weeks' treatment with active transdermal nicotine patches or placebo and brief counselling at monthly visits. Sustained smoking cessation for the 28 days before the visit at week 12 verified by expired carbon monoxide concentrations. At 12 weeks 21/315 (6.7%) subjects allocated to active treatment had stopped smoking compared with 6/314 (1.9%) allocated to placebo (absolute difference 4.7% 95% confidence interval 1.6% to 7.9% P = 0.003). At 26 weeks the rates were 20/315 (6.4%) and 8/314 (2.6%) (3.8% 0.6% to 7.0% P = 0.021). Difficulty in sleeping was reported by 43/179 (24.0%) on active treatment and 19/143 (13.3%) on placebo (P = 0.015). Severe reactions at the site of application were rare (6/322 1.9%). Repeated treatment with transdermal nicotine together with brief counselling can improve the low success rates of smoking cessation in recently relapsed, moderate to heavy smokers. Questions remain about whether more intensive interventions or higher doses of nicotine could be more effective. The likelihood of severe reactions at the site of application with repeated treatment is low.
Publisher: Elsevier BV
Date: 07-1995
Publisher: AIP Publishing
Date: 21-04-2023
DOI: 10.1063/5.0142302
Abstract: Peptide self-assembly is the process by which peptide molecules aggregate into low dimensional (1D, 2D) or 3D ordered materials with potential applications ranging from drug delivery to electronics. Short peptides are particularly good candidates for forming supramolecular assemblies due to the relatively simple structure and ease of modulating their self-assembly process to achieve required material properties. The experimental resolution of fibrous peptide-based nanomaterials as 3D atomic coordinates remains challenging. For surface-mediated peptide assembly in particular, it is typically not feasible to resolve multiple conformationally distinct surface bound peptide structures by experiment. The mechanisms of peptide self-assembly also remain elusive due to the interchange of complex interactions and multiple time and length scales involved in the self-assembly process. Peptide self-assembly in solution, or mediated by surfaces, is driven by specific interactions between the peptides and water, competing interactions within the peptide and/or between peptide aggregate units and, in the latter case, an interplay of the interactions between peptides and solvent molecules for adsorption onto a proximal surface. Computational methodologies have proven beneficial in elucidating the structures formed during peptide self-assembly and the molecular mechanisms driving it, and hence have scope in facilitating the development of functional peptide-based nanomaterials for medical or biotechnological applications. In this perspective, computational methods that have provided molecular insights into the mechanisms of formation of peptide biomaterials, and the all-atom-resolved structures of peptide assemblies are presented. Established and recently emerged molecular simulation approaches are reviewed with a focus on applications relevant to peptide assembly, including all-atom and coarse-grained “brute force” molecular dynamics methods as well as the enhanced s ling methodologies: umbrella s ling, steered and replica exchange molecular dynamics, and variants of metadynamics. These approaches have been shown to contribute all-atom details not yet available experimentally, to advance our understanding of peptide self-assembly processes and biomaterial formation. The scope of this review includes a summary of the current state of the computational methods, in terms of their strengths and limitations for application to self-assembling peptide biomaterials.
Publisher: American Chemical Society (ACS)
Date: 18-09-2018
DOI: 10.1021/ACSCHEMBIO.8B00561
Abstract: SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( K
Publisher: American Chemical Society (ACS)
Date: 29-04-2020
Publisher: American Chemical Society (ACS)
Date: 13-02-0001
Publisher: Bentham Science Publishers Ltd.
Date: 07-06-2017
Publisher: American Chemical Society (ACS)
Date: 03-03-2021
Publisher: American Medical Association (AMA)
Date: 25-09-1996
Publisher: American Chemical Society (ACS)
Date: 06-07-2020
Publisher: Wiley
Date: 06-07-2018
Abstract: The p75 splice variant of lens epithelium-derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre-integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X-ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV-1 integrase core domain. Although the X-ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low-energy solution and bound conformations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1996
Publisher: Elsevier BV
Date: 08-1996
DOI: 10.1016/S0002-9149(96)00331-1
Abstract: Nonrheumatic atrial fibrillation (AF) frequently coexists with other risk factors for cerebral ischemia. This study was originally designed to determine which combinations of clinical and echocardiographic abnormalities were most closely associated with the risk of cerebral ischemic events. Patients with cerebral ischemic events (n = 214) and community-based control subjects (n = 201) underwent transesophageal echocardiography and carotid artery imaging. Adjusted odds ratios (ORs) were determined using multiple logistic regression analysis. Independent risk factors for cerebral ischemia included diabetes, carotid stenosis, aortic sclerosis, left ventricular dysfunction, left ventricular hypertrophy, left atrial (LA) spontaneous contrast, and proximal aortic atheroma. Nonrheumatic AF in combination with LA spontaneous contrast and LA enlargement showed a strong association with cerebral ischemic events (OR 33.7 [95% confidence interval 4.53 to 251]). In subjects with sinus rhythm or nonrheumatic AF, LA enlargement was not associated with an increased risk of cerebral ischemic events in the absence of LA spontaneous contrast. However, only 2 patients and 1 control subject had nonrheumatic AF without LA spontaneous contrast or LA enlargement. Therefore, study of a larger number of subjects is required to address the issue of whether nonrheumatic AF itself carries increased risk. The combination of nonrheumatic AF with LA spontaneous contrast is a potent risk factor for cerebral ischemia. Ascertaining the risk factor in nonrheumatic AF requires adequate examination for underlying cardiac, aortic, and carotid vascular disease. Transesophageal echocardiography may contribute to this assessment.
Publisher: American Chemical Society (ACS)
Date: 30-09-2022
Abstract: The ability to predict cell-permeable candidate molecules has great potential to assist drug discovery projects. Large molecules that lie beyond the Rule of Five (bRo5) are increasingly important as drug candidates and tool molecules for chemical biology. However, such large molecules usually do not cross cell membranes and cannot access intracellular targets or be developed as orally bioavailable drugs. Here, we describe a random forest (RF) machine learning model for the prediction of passive membrane permeation rates developed using a set of over 1000 bRo5 macrocyclic compounds. The model is based on easily calculated chemical features/descriptors as independent variables. Our random forest (RF) model substantially outperforms a multiple linear regression model based on the same features and achieves better performance metrics than previously reported models using the same underlying data. These features include: (1) polar surface area in water, (2) the octanol-water partitioning coefficient, (3) the number of hydrogen-bond donors, (4) the sum of the topological distances between nitrogen atoms, (5) the sum of the topological distances between nitrogen and oxygen atoms, and (6) the multiple molecular path count of order 2. The last three features represent molecular flexibility, the ability of the molecule to adopt different conformations in the aqueous and membrane interior phases, and the molecular "chameleonicity." Guided by the model, we propose design guidelines for membrane-permeating macrocycles. It is anticipated that this model will be useful in guiding the design of large, bioactive molecules for medicinal chemistry and chemical biology applications.
Publisher: BMJ
Date: 05-1996
Publisher: Elsevier BV
Date: 03-1995
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1440-1681.1997.TB01225.X
Abstract: 1. Hormone replacement therapy (HRT) with oestrogen or oestrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima-medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non-HRT) and those women on long-term HRT with oestrogen alone (HRT-E) or oestrogen plus progestin (HRT-EP). 2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure. 3. Plasma total cholesterol was reduced and high-density lipoprotein-cholesterol was increased in the HRT group compared with the non-HRT group low-density lipoprotein-cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT-E and HRT-EP subgroups were similar. 4. Carotid IMT was significantly reduced in the HRT group compared with men and non-HRT groups. Results for HRT-E and HRT-EP subgroups were similar. 5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age SAC was higher in both HRT-E and HRT-EP groups compared with the non-HRT group. Indices of carotid stiffness were similar in men and in non-HRT groups. The HRT-EP group showed increased carotid stiffness compared with the HRT-E group. 6. There is an apparent protective effect of long-term oestrogen therapy on carotid IMT and age-related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.
Location: Australia
No related grants have been discovered for Billy Williams-Noonan.