Drug and Alcohol Rehabilitation: MycPermCheck: The Mycobacterium Tuberculosis Permeability Prediction Tool for Small Molecules.

MycPermCheck: The Mycobacterium tuberculosis permeability prediction tool for small molecules.

Filed under: Drug and Alcohol Rehabilitation

Bioinformatics. 2012 Oct 25;
Merget B, Zilian D, Müller T, Sotriffer CA

MOTIVATION: With over 8 million new cases in 2010, particularly documented in developing countries, tuberculosis (TB) is still a highly present pandemic and often terminal. This is also due to the emergence of antibiotic-resistant strains (MDR-TB and XDR-TB) of the primary causative TB agent Mycobacterium tuberculosis (MTB). Efforts to develop new effective drugs against MTB are restrained by the unique and largely impermeable composition of the mycobacterial cell wall. RESULTS: Based on a database of antimycobacterial substances (CDD TB) 3,815 compounds were classified as active and thus permeable. A data mining approach was conducted to gather the physico-chemical similarities of these substances and delimit them from a generic dataset of drug-like molecules. On the basis of the differences in these datasets, a regression model was generated and implemented into the online tool MycPermCheck to predict the permeability probability of small organic compounds.Discussion: Given the current lack of precise molecular criteria determining mycobacterial permeability, MycPermCheck represents an unprecedented prediction tool intended to support antimycobacterial drug discovery. It follows a novel knowledge-driven approach to estimate the permeability probability of small organic compounds. As such, MycPermCheck can be used intuitively as an additional selection criterion for potential new inhibitors against Mycobacterium tuberculosis. Based on the validation results, its performance is expected to be of high practical value for virtual screening purposes. AVAILABILITY: The online tool is freely accessible under the URL http://www.mycpermcheck.aksotriffer.pharmazie.uni-wuerzburg.de CONTACT: sotriffer@uni-wuerzburg.de.
HubMed – drug

 

Introducing Drugster: a comprehensive and fully integrated drug design, lead and structure optimization toolkit.

Filed under: Drug and Alcohol Rehabilitation

Bioinformatics. 2012 Oct 25;
Vlachakis D, Tsagrasoulis D, Megalooikonomou V, Kossida S

SUMMARY: Drugster is a fully interactive pipeline designed to break the command line barrier and introduce a new user-friendly environment to perform drug design, lead and structure optimization experiments through an efficient combination of the PDB2PQR, Ligbuilder, Gromacs and Dock suites. Our platform features a novel workflow that guides the user through each logical step of the iterative 3D structural optimization setup and drug design process, by providing a seamless interface to all incorporated packages. AVAILABILITY: Drugster can be freely downloaded via our dedicated server system at http://www.bioacademy.gr/bioinformatics/drugster/. CONTACT: For support, comments and bug reports please contact: dvlachakis@bioacademy.gr.
HubMed – drug

 

Effect of cardiac resynchronization therapy and implantable cardioverter defibrillator on quality of life in patients with heart failure: a meta-analysis.

Filed under: Drug and Alcohol Rehabilitation

Europace. 2012 Nov; 14(11): 1602-7
Chen S, Yin Y, Krucoff MW

To compare the improvement of quality of life (QoL) in cardiac resynchronization therapy plus implantable cardioverter defibrillator (CRT-D) therapy with that in implantable cardioverter defibrillator (ICD) therapy alone for patients with heart failure.Medline, Embase, The Cochrane Library, and US Food and Drug Administration website were searched for published studies up to 31 December 2011. Studies were considered for inclusion if they were randomized controlled trials (RCTs) that compared the efficacy of CRT-D therapy with ICD therapy in patients with heart failure. The primary outcome of this study was improvement in QoL. Four RCTs with 1655 patients were included in this meta-analysis. Overall, the QoL score of patients in CRT-D group significantly improved [weighted mean difference (WMD): -6.02; 95% confidence interval (CI): -10.56 to -1.48] compared with that in the ICD only group. However, the benefit with respect to QoL in CRT-D group was not maintained when subset meta-analysis was performed in patients with New York Heart Association (NYHA) class I-II (WMD: 0.19; 95% CI: -3.89 to 4.72), whereas the patients with NYHA class III-IV in CRT-D group still experienced a significant improvement of QoL score compared with ICD group (WMD: -8.49; 95% CI: -13.39 to -3.59).CRT-D therapy improves the QoL compared with ICD therapy alone, especially in patients with moderate to severe heart failure.
HubMed – drug

 

Characterizing functional domains of the SloR metalloregulatory protein in Streptococcus mutans.

Filed under: Drug and Alcohol Rehabilitation

J Bacteriol. 2012 Oct 26;
Haswell JR, Pruitt BW, Cornacchione LP, Coe CL, Smith EG, Spatafora GA

Streptococcus mutans is a commensal member of the healthy plaque biofilm and the primary causative agent of dental caries. The present study is an investigation of SloR, a 25-kDa metalloregulatory protein that modulates genes responsible for S. mutans-induced cariogenesis. Previous studies of SloR homologues in other bacterial pathogens have identified three domains critical to repressor functionality: an N-terminal DNA-binding domain, a central dimerization domain, and a C-terminal FeoA (previously SH3-like) domain. We used site-directed mutagenesis to identify critical amino acid residues within each of these domains of the SloR protein. Select residues were targeted for mutagenesis and non-conservative amino acid substitutions were introduced by overlap extension PCR. Furthermore, three C-terminally truncated SloR variants were generated using conventional PCR. The repressor functionality and DNA-binding ability of each variant was assessed using CAT reporter gene assays, real time qRT-PCR, and electrophoretic mobility shift assays. We identified 12 residues within SloR that cause significant de-repression of sloABC promoter activity (P<0.05) compared to wild-type SloR. De-repression was particularly noteworthy in metal ion-binding site 1 mutants, consistent with the site's importance in gene repression by SloR. In addition, a hyperactive SloR(E169A/Q170A) mutant was identified as having significantly heightened repression of sloABC promoter activity, and experiments with C-terminal deletion mutants support involvement of the FeoA domain in SloR-mediated gene repression. Given these results, we describe the functional domains of the S. mutans SloR protein and propose that the hyperactive mutant could serve as a target for rational drug design aimed at repressing SloR-mediated virulence gene expression. HubMed – drug

 

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