Structural diversity of biologically interesting datasets: a scaffold analysis approach

ABSTRACT:The recent public availability of the human metabolome and natural product datasets has revitalized "metabolite-likeness" and "natural product-likeness" as a drug design concept to design lead libraries targeting specific pathways. Many reports have analyzed the physicochemical property space of biologically important datasets, with only a few comprehensively characterizing the scaffold diversity in public datasets of biological interest. With large collections of high quality public data currently available, we carried out a comparative analysis of current day leads with other biologically relevant datasets.In this study, we note a two-fold enrichment of metabolite scaffolds in drug dataset (42%) as compared to currently used lead libraries (23%). We also note that only a small percentage (5%) of natural product scaffolds space is shared by the lead dataset. We have identified specific scaffolds that are present in metabolites and natural products, with close counterparts in the drugs, but are missing in the lead dataset. To determine the distribution of compounds in physicochemical property space we analyzed the molecular polar surface area, the molecular solubility, the number of rings and the number of rotatable bonds in addition to four well-known Lipinski properties. Here, we note that, with only few exceptions, most of the drugs follow Lipinski's rule. The average values of the molecular polar surface area and the molecular solubility in metabolites is the highest while the number of rings is the lowest. In addition, we note that natural products contain the maximum number of rings and the rotatable bonds than any other dataset under consideration.Currently used lead libraries make little use of the metabolites and natural products scaffold space. We believe that metabolites and natural products are recognized by at least one protein in the biosphere therefore, sampling the fragment and scaffold space of these compounds, along with the knowledge of distribution in physicochemical property space, can result in better lead libraries. Hence, we recommend the greater use of metabolites and natural products while designing lead libraries. Nevertheless, metabolites have a limited distribution in chemical space that limits the usage of metabolites in library design.14 page(s

Physiochemical property space distribution among human metabolites, drugs and toxins

<p>Abstract</p> <p>Background</p> <p>The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's "rule of five" (Ro5). For over a decade, Ro5 has been applied to combinatorial compounds, drugs and ligands, in the search for suitable lead compounds. Unfortunately, till date, a clear distinction between drugs and non-drugs has not been achieved. The current trend is to seek out drugs which show metabolite-likeness. In identifying similar physicochemical characteristics, compounds have usually been clustered based on some characteristic, to reduce the search space presented by large molecular datasets. This paper examines the similarity of current drug molecules with human metabolites and toxins, using a range of computed molecular descriptors as well as the effect of comparison to clustered data compared to searches against complete datasets.</p> <p>Results</p> <p>We have carried out statistical and substructure functional group analyses of three datasets, namely human metabolites, drugs and toxin molecules. The distributions of various molecular descriptors were investigated. Our analyses show that, although the three groups are distinct, present-day drugs are closer to toxin molecules than to metabolites. Furthermore, these distributions are quite similar for both clustered data as well as complete or unclustered datasets.</p> <p>Conclusion</p> <p>The property space occupied by metabolites is dissimilar to that of drugs or toxin molecules, with current drugs showing greater similarity to toxins than to metabolites. Additionally, empirical rules like Ro5 can be refined to identify drugs or drug-like molecules that are clearly distinct from toxic compounds and more metabolite-like. The inclusion of human metabolites in this study provides a deeper insight into metabolite/drug/toxin-like properties and will also prove to be valuable in the prediction or optimization of small molecules as ligands for therapeutic applications.</p

Determination of consensus among professionals for community safety terms through a Delphi study

This is a post-peer-review, pre-copyedit version of an article published in Crime Prevention and Community Safety. The definitive publisher-authenticated version 2013, 15(4), pp. 258-277 is available online at: http://dx.doi.org/10.1057/cpcs.2013.9This article reports the findings from a study of Community Safety professionals (Academics, Policymakers and Practitioners), using the Delphi method to determine common definitions, if any, for Community Safety terms in current usage. The study investigated the differences in the way that the terms were used and understood by the members of the three groups. The study was predicated on the view that the groups of Community Safety professionals probably use the language of Community Safety in different ways. It is suggested that work in the field would benefit from a shared terminology, where the same term has the same meaning for different professional groups

Right ventricular function declines after cardiac surgery in adult patients with congenital heart disease

Right ventricular function (RVF) is often selectively declined after coronary artery bypass graft surgery. In adult patients with congenital heart disease (CHD) the incidence and persistence of declined RVF after cardiac surgery is unknown. The current study aimed to describe RVF after cardiac surgery in these patients. Adult CHD patients operated between January 2008 and December 2009 in the Academic Medical Centre in Amsterdam were studied. Clinical characteristics, laboratory tests, surgical data and intensive care unit outcome were obtained from medical records. RVF was measured by trans-thoracic echocardiography (TTE) and expressed by tricuspid annular plane systolic excursion (TAPSE), tissue Doppler imaging (RV S’) and myocardial performance index (MPI) pre-operatively and direct, at intermediate and late follow up. Of a total of 185 operated, 86 patients (mean age 39 ± 13 years, 54% male) had echo data available. There was a significant fall in RVF after cardiac surgery. TAPSE and RV S’ were significantly higher and MPI was significantly lower pre-operatively compared to direct post-operative values (TAPSE 22 ± 5 versus 13 ± 3 mm (P < 0.01), RV S’ 11 ± 4 versus 8 ± 2 cm/s (P < 0.01) and MPI 0.36 ± 0.14 vs 0.62 ± 0.25; P < 0.01). There were no significant differences in left ventricular function pre-operatively compared to post-operative values. Right-sided surgery was performed in 33, left-sided surgery in 37 and both sided surgery in 16 patients. Decline in RVF was equal for those groups. Patients with severe decline in RVF, were patients who underwent tricuspid valve surgery. Decline in RVF was associated with post-operative myocardial creatine kinase level and maximal troponin T level. There was no association between decline in RVF and clinical outcome on the intensive care unit. 18 months post-operatively, most RVF parameters had recovered to pre-operative values, but TAPSE which remained still lower (P < 0.01). CHD patients have a decline in RVF directly after cardiac surgery, regardless the side of surgery. Although a gradual improvement was observed, complete recovery was not seen 18 months post-operatively

Barriers to effective diabetes management – a survey of people with severe mental illness

Background: People with severe mental illnesses (SMI) such as schizophrenia and bipolar disorder have an increased risk of developing type 2 diabetes and have poorer health outcomes than those with diabetes alone. To maintain good diabetes control, people with diabetes are advised to engage in several self-management behaviours. The aim of this study was to identify barriers or enablers of diabetes self-management experienced by people with SMI. Methods: Adults with type 2 diabetes and SMI were recruited through UK National Health Service organisations and mental health and diabetes charities. Participants completed an anonymous survey consisting of: Summary of Diabetes Self-Care Activities (SDSCA); CORE-10 measure of psychological distress; a measure of barriers and enablers of diabetes self-management based on the Theoretical Domains Framework; Diabetes UK care survey on receipt of 14 essential aspects of diabetes healthcare. To identify the strongest explanatory variables of SDSCA outcomes, significant variables (p < .05) identified from univariate analyses were entered into multiple regressions. Results: Most of the seventy-seven participants had bipolar disorder (42%) or schizophrenia (36%). They received a mean of 7.6 (SD 3.0) diabetes healthcare essentials. Only 28.6% had developed a diabetes care plan with their health professional and only 40% reported receiving specialist psychological support. Engagement in self-management activities was variable. Participants reported taking medication on 6.1 (SD 2.0) days in the previous week but other behaviours were less frequent: general diet 4.1 (2.3) days; specific diet 3.6 (1.8) days, taking exercise 2.4 (2.1) days and checking feet on 1.7 (1.8) days. Smoking prevalence was 44%. Participants reported finding regular exercise and following a healthy diet particularly difficult. Factors associated with diabetes self22 management included: the level of diabetes healthcare and support received; emotional wellbeing; priority given to diabetes; perceived ability to manage diabetes or establish a routine to do so; and perceived consequences of diabetes self-management. Conclusions: Several aspects of diabetes healthcare and self-management are suboptimal in people with SMI. There is a need to improve diabetes self-management support for this population by integrating diabetes action plans into care planning and providing adequate psychological support to help people with SMI manage their diabetes

Life Expectancy at Birth for People with Serious Mental Illness and Other Major Disorders from a Secondary Mental Health Care Case Register in London

Despite improving healthcare, the gap in mortality between people with serious mental illness (SMI) and general population persists, especially for younger age groups. The electronic database from a large and comprehensive secondary mental healthcare provider in London was utilized to assess the impact of SMI diagnoses on life expectancy at birth.People who were diagnosed with SMI (schizophrenia, schizoaffective disorder, bipolar disorder), substance use disorder, and depressive episode/disorder before the end of 2009 and under active review by the South London and Maudsley NHS Foundation Trust (SLAM) in southeast London during 2007-09 comprised the sample, retrieved by the SLAM Case Register Interactive Search (CRIS) system. We estimated life expectancy at birth for people with SMI and each diagnosis, from national mortality returns between 2007-09, using a life table method.A total of 31,719 eligible people, aged 15 years or older, with SMI were analyzed. Among them, 1,370 died during 2007-09. Compared to national figures, all disorders were associated with substantially lower life expectancy: 8.0 to 14.6 life years lost for men and 9.8 to 17.5 life years lost for women. Highest reductions were found for men with schizophrenia (14.6 years lost) and women with schizoaffective disorders (17.5 years lost).The impact of serious mental illness on life expectancy is marked and generally higher than similarly calculated impacts of well-recognised adverse exposures such as smoking, diabetes and obesity. Strategies to identify and prevent causes of premature death are urgently required

Care for patients with severe mental illness: the general practitioner's role perspective

BACKGROUND: Patients with severe mental illness (SMI) experience distress and disabilities in several aspects of life, and they have a higher risk of somatic co-morbidity. Both patients and their family members need the support of an easily accessible primary care system. The willingness of general practitioners and the impeding factors for them to participate in providing care for patients with severe mental illness in the acute and the chronic or residual phase were explored. METHODS: A questionnaire survey of a sample of Dutch general practitioners spread over the Netherlands was carried out. This comprised 20 questions on the GP's 'Opinion and Task Perspective', 19 questions on 'Treatment and Experiences', and 27 questions on 'Characteristics of the General Practitioner and the Practice Organisation'. RESULTS: 186 general practitioners distributed over urban areas (49%), urbanised rural areas (38%) and rural areas (15%) of the Netherlands participated. The findings were as follows: GPs currently considered themselves as the first contact in the acute psychotic phase. In the chronic or residual phase GPs saw their core task as to diagnose and treat somatic co-morbidity. A majority would be willing to monitor the general health of these patients as well. It appeared that GP trainers and GPs with a smaller practice setting made follow-up appointments and were willing to monitor the self-care of patients with SMI more often than GPs with larger practices.GPs also saw their role as giving support and information to the patient's family.However, they felt a need for recognition of their competencies when working with mental health care specialists. CONCLUSION: GPs were willing to participate in providing care for patients with SMI. They considered themselves responsible for psychotic emergency cases, for monitoring physical health in the chronic phase, and for supporting the relatives of psychotic patients

Integrating an internet-mediated walking program into family medicine clinical practice: a pilot feasibility study

<p>Abstract</p> <p>Background</p> <p>Regular participation in physical activity can prevent many chronic health conditions. Computerized self-management programs are effective clinical tools to support patient participation in physical activity. This pilot study sought to develop and evaluate an online interface for primary care providers to refer patients to an Internet-mediated walking program called Stepping Up to Health (SUH) and to monitor participant progress in the program.</p> <p>Methods</p> <p>In Phase I of the study, we recruited six pairs of physicians and medical assistants from two family practice clinics to assist with the design of a clinical interface. During Phase II, providers used the developed interface to refer patients to a six-week pilot intervention. Provider perspectives were assessed regarding the feasibility of integrating the program into routine care. Assessment tools included quantitative and qualitative data gathered from semi-structured interviews, surveys, and online usage logs.</p> <p>Results</p> <p>In Phase I, 13 providers used SUH and participated in two interviews. Providers emphasized the need for alerts flagging patients who were not doing well and the ability to review participant progress. Additionally, providers asked for summary views of data across all enrolled clinic patients as well as advertising materials for intervention recruitment. In response to this input, an interface was developed containing three pages: 1) a recruitment page, 2) a summary page, and 3) a detailed patient page. In Phase II, providers used the interface to refer 139 patients to SUH and 37 (27%) enrolled in the intervention. Providers rarely used the interface to monitor enrolled patients. Barriers to regular use of the intervention included lack of integration with the medical record system, competing priorities, patient disinterest, and physician unease with exercise referrals. Intention-to-treat analyses showed that patients increased walking by an average of 1493 steps/day from pre- to post-intervention (<it>t </it>= (36) = 4.13, <it>p </it>< 0.01).</p> <p>Conclusions</p> <p>Providers successfully referred patients using the SUH provider interface, but were less willing to monitor patient compliance in the program. Patients who completed the program significantly increased their step counts. Future research is needed to test the effectiveness of integrating SUH with clinical information systems over a longer evaluation period.</p