Optical monitoring of gamma-ray source fields

The three gamma-ray burst source fields GBS1028+46, GBS1205+24, and GBS2252-03 have been monitored for transient optical emission for a combined total of 52 hours. No optical events were seen. The limiting magnitude for the search was M sub V = 15.8 longer and M sub V = 17.0 for 6.0 s or longer

The effects of combinatorial chemistry and technologies on drug discovery and biotechnology : A mini review

The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of "combinatorial thinking" in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided

Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)- glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease

Connecting Peptide Physicochemical and Antimicrobial Properties by a Rational Prediction Model

The increasing rate in antibiotic-resistant bacterial strains has become an imperative health issue. Thus, pharmaceutical industries have focussed their efforts to find new potent, non-toxic compounds to treat bacterial infections. Antimicrobial peptides (AMPs) are promising candidates in the fight against antibiotic-resistant pathogens due to their low toxicity, broad range of activity and unspecific mechanism of action. In this context, bioinformatics' strategies can inspire the design of new peptide leads with enhanced activity. Here, we describe an artificial neural network approach, based on the AMP's physicochemical characteristics, that is able not only to identify active peptides but also to assess its antimicrobial potency. The physicochemical properties considered are directly derived from the peptide sequence and comprise a complete set of parameters that accurately describe AMPs. Most interesting, the results obtained dovetail with a model for the AMP's mechanism of action that takes into account new concepts such as peptide aggregation. Moreover, this classification system displays high accuracy and is well correlated with the experimentally reported data. All together, these results suggest that the physicochemical properties of AMPs determine its action. In addition, we conclude that sequence derived parameters are enough to characterize antimicrobial peptides

Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Thymidine monophosphate kinase (TMPK(mt)) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2',3'-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2',3'-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK(mt) binding site. The three-dimensional structure of the TMPK(mt) complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK(mt) target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties

DESIGN OF PEPTIDOMIMETIC INHIBITORS OF ASPARTIC PROTEASE OF HIV-1 CONTAINING -PHEpsiPRO- CORE AND DISPLAYING FAVOURABLE ADME-RELATED PROPERTIES

Aspartic protease (PR) of HIV-1 virus represents a valid therapeutic target for the design of antiviral agents suitable for treatment of AIDS.We have designed peptidomimetic PR inhibitors containing a novel dihydroxyethylenediamine \u2013Phe-C[CHOH\u2013CHOH]-Pro\u2013 core using molecular modelling approach that predicts the inhibitory potencies (ICpre 50 ) in terms of computed relative enzyme\u2013inhibitor complexation Gibbs free energies (DDGcomp). The modelling approach considers not only the enzyme\u2013inhibitor interactions, but includes also the solvent and entropic effects affecting the enzyme inhibition. The objectives of this study were to optimize the number and type of flanking residues that occupy the S3, S2 and S20, S30 positions in the PR binding pocket and to select potent lead candidates, which display also favourable ADME-related properties. The structure-based designwas combined with a synthetic strategy used to prepare a training set of 10 analogues sharing the \u2013PheCPro\u2013 core. This strategy couples stereochemical control with full flexibility in the choice of the flanking residues and in vitro activity assays. A QSAR model correlating calculated DDGcomp with the measured ICexp 50 values for the training set was prepared and confirmed that our computational approach can serve for reliable prediction of PR inhibitory potencies of peptidomimetics. The appropriate choice of the flanking residues allowed us to design virtual lead compounds, such as FP14, FP23 and FP76, with reduced molecular weight, predicted inhibitory potencies in the picomolar range, promising ADME profiles and a potential to escape drug resistance due to favourable interactions with the PR backbone