Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma monsoni, one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 mu M. The most potent inhibitors 7, 10, and 17 with 1050 of 2, 18, and 38 mu M, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.

Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: Discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole

In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4 (3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3- benzodioxolyl-N- acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive pro. le more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile (C) 2009 Elsevier Ltd. All rights reserved.

Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors

A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.

Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery

The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with K(i)(app) value of 19.28 mu M and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development. (C) 2010 Elsevier Masson SAS. All rights reserved.

Discovery of Phthalimides as Immunomodulatory and Antitumor Drug Prototypes

Brazilian National Council of Research (CNPq)[471834/2006-8]

Assessing the Design of the Library's Discovery Interface and Online resources: A Case Study at the University of Maryland

This presentation was offered as part of the CUNY Library Assessment Conference, Reinventing Libraries: Reinventing Assessment, held at the City University of New York in June 2014.

Cathepsin S as a biomarker of low-grade inflammation, insulin resistance, and cardiometabolic disease risk

Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.    The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.    This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.    In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.    Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations. 

Semantic and Personalised Service Discovery

One of the most pervasive classes of services needed to support e-Science applications are those responsible for the discovery of resources. We have developed a solution to the problem of service discovery in a Semantic Web/Grid setting. We do this in the context of bioinformatics, which is the use of computational and mathematical techniques to store, manage, and analyse the data from molecular biology in order to answer questions about biological phenomena. Our specific application is myGrid (www.mygrid.org.uk) that is developing open source, service-based middleware upon which bioinformatics applications can be built. myGrid is specifically targeted at developing open source high-level service Grid middleware for bioinformatics.

Semantic and Personalised Service Discovery

One of the most pervasive classes of services needed to support e-Science applications are those responsible for the discovery of resources. We have developed a solution to the problem of service discovery in a Semantic Web/Grid setting. We do this in the context of bioinformatics, which is the use of computational and mathematical techniques to store, manage, and analyse the data from molecular biology in order to answer questions about biological phenomena. Our specific application is myGrid (http: //www.mygrid.org.uk) that is developing open source, service-based middleware upon which bioin- formatics applications can be built. myGrid is specif- ically targeted at developing open source high-level service Grid middleware for bioinformatics.

Personalised Grid Service Discovery

The authors take a broad view that ultimately Grid- or Web-services must be located via personalised, semantic-rich discovery processes. They argue that such processes must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. Examples of such metadata are reliability metrics, quality of service data, or semantic service description markup. This paper presents UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. They also discuss the use of a rich, graph-based RDF query language for syntactic queries on this data. Finally, they analyse the performance of each of these contributions in our implementation.

Personalised Grid Service Discovery

We take a broad view that ultimately Grid- or Web-services must be located via personalised, semantic-rich discovery processes. We argue that such processes must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. Examples of such metadata are reliability metrics, quality of service data, or semantic service description markup. This paper presents UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. We also discuss the use of a rich, graph-based RDF query language for syntactic queries on this data. Finally, we analyse the performance of each of these contributions in our implementation.

Towards a Protocol for the Attachment of Metadata to Service Descriptions and its Use in Semantic Discovery

Service discovery in large scale, open distributed systems is difficult because of the need to filter out services suitable to the task at hand from a potentially huge pool of possibilities. Semantic descriptions have been advocated as the key to expressive service discovery, but the most commonly used service descriptions and registry protocols do not support such descriptions in a general manner. In this paper, we present a protocol, its implementation and an API for registering semantic service descriptions and other task/user-specific metadata, and for discovering services according to these. Our approach is based on a mechanism for attaching structured and unstructured metadata, which we show to be applicable to multiple registry technologies. The result is an extremely flexible service registry that can be the basis of a sophisticated semantically-enhanced service discovery engine, an essential component of a Semantic Grid.

Agents and the Grid: Service Discovery

The Grid is a large-scale computer system that is capable of coordinating resources that are not subject to centralised control, whilst using standard, open, general-purpose protocols and interfaces, and delivering non-trivial qualities of service. In this chapter, we argue that Grid applications very strongly suggest the use of agent-based computing, and we review key uses of agent technologies in Grids: user agents, able to customize and personalise data; agent communication languages offering a generic and portable communication medium; and negotiation allowing multiple distributed entities to reach service level agreements. In the second part of the chapter, we focus on Grid service discovery, which we have identified as a prime candidate for use of agent technologies: we show that Grid-services need to be located via personalised, semantic-rich discovery processes, which must rely on the storage of arbitrary metadata about services that originates from both service providers and service users. We present UDDI-MT, an extension to the standard UDDI service directory approach that supports the storage of such metadata via a tunnelling technique that ties the metadata store to the original UDDI directory. The outcome is a flexible service registry which is compatible with existing standards and also provides metadata-enhanced service discovery.

Principles of Personalisation of Service Discovery

We define personalisation as the set of capabilities that enables a user or an organisation to customise their working environment to suit their specific needs, preferences and circumstances. In the context of service discovery on the Grid, the demand for personalisation comes from individual users, who want their preferences to be taken into account during the search and selection of suitable services. These preferences can express, for example, the reliability of a service, quality of results, functionality, and so on. In this paper, we identify the problems related to personalising service discovery and present our solution: a personalised service registry or View. We describe scenarios in which personsalised service discovery would be useful and describe how our technology achieves them.