SwissTargetPrediction: a web server for target prediction of bioactive small molecules

Bioactive small molecules, such as drugs or metabolites, bind to proteins or other macro-molecular targets to modulate their activity, which in turn results in the observed phenotypic effects. For this reason, mapping the targets of bioactive small molecules is a key step toward unraveling the molecular mechanisms underlying their bioactivity and predicting potential side effects or cross-reactivity. Recently, large datasets of protein-small molecule interactions have become available, providing a unique source of information for the development of knowledge-based approaches to computationally identify new targets for uncharacterized molecules or secondary targets for known molecules. Here, we introduce SwissTargetPrediction, a web server to accurately predict the targets of bioactive molecules based on a combination of 2D and 3D similarity measures with known ligands. Predictions can be carried out in five different organisms, and mapping predictions by homology within and between different species is enabled for close paralogs and orthologs. SwissTargetPrediction is accessible free of charge and without login requirement at http://www.swisstargetprediction.c

Molecular Electrocatalysis for Oxygen Reduction by Cobalt Porphyrins Adsorbed at Liquid/Liquid Interfaces

Molecular electrocatalysis for oxygen reduction at a polarized water/1,2-dichloroethane (DCE) interface was studied, involving aqueous protons, ferrocene (Fc) in DCE and amphiphilic cobalt porphyrin catalysts adsorbed at the interface. The catalyst, (2,8,13,17-tetraethyl-3,7,12,18-tetramethyl-5-p-aminophenylporphyrin) cobalt(II) (CoAP), functions like conventional cobalt porphyrins, activating 02 via coordination by the formation of a superoxide structure. Furthermore, due to the hydrophilic nature of the aminophenyl group, CoAP has a strong affinity for the water/DCE interface as evidenced by lipophilicity mapping calculations and surface tension measurements, facilitating the protonation of the CoAP-O-2 complex and its reduction by ferrocene. The reaction is electrocatalytic as its rate depends on the applied Galvani potential difference between the two phases

Mutagenesis and Functional Studies with Succinate Dehydrogenase Inhibitors in the Wheat Pathogen Mycosphaerella graminicola

A range of novel carboxamide fungicides, inhibitors of the succinate dehydrogenase enzyme (SDH, EC 1.3.5.1) is currently being introduced to the crop protection market. The aim of this study was to explore the impact of structurally distinct carboxamides on target site resistance development and to assess possible impact on fitness

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Stereoselective block of hERG channel by bupivacaine scrutinized at molecular level

In the heart, the hERG voltage-gated potassium channel mediates the IKr current, which is crucial for the duration of cardiac action potential. Undesired block of the channel may prolong the QT interval with increased risk of malignant ventricular arrhythmia called torsades de pointes. Although the molecular determinants of hERG block are intensively studied, stereoselectivity has been poorly investigated. Levo-(S)-bupivacaine was the first drug reported to have higher affinity for hERG than its enantiomer. This study aims at understanding the principles underlying the stereoselectivity of bupivacaine block with the help of molecular modeling. Putative binding modes of levo-(S)- and dextro-(R)-bupivacaine inside an open form model of hERG channel were predicted by docking simulations, allowing a clear depiction of ligand-protein interactions. Estimated binding energies for both enantiomers to wild-type channel are in line with previously published electrophysiology measurements. These results may be considered as a confirmation at the molecular level of bupivacaine stereoselective binding towards hERG. Moreover this information lays the foundations for a structural guideline to filter out potentially cardiotoxic drug candidates in silico

Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization

The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico

iLOGP: A Simple, Robust, and Efficient Description of <i>n</i>‑Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach

The <i>n</i>-octanol/water partition coefficient (log <i>P</i>_o/w) is a key physicochemical parameter for drug discovery, design, and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log <i>P</i>_o/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the <i>Martel</i> druglike test set, the predictive power of the best model (<i>N</i> = 706, <i>r</i> = 0.64, MAE = 1.18, and RMSE = 1.40) is similar to six well-established empirical methods. On the <i>17-drug</i> test set, our model outperformed all compared empirical methodologies (<i>N</i> = 17, <i>r</i> = 0.94, MAE = 0.38, and RMSE = 0.52). The physical basis of our original GB/SA approach together with its predictive capacity, computational efficiency (1 to 2 s per molecule), and tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log <i>P</i> method (iLOGP), to complement the portfolio of drug design tools developed and provided by the SIB Swiss Institute of Bioinformatics

The medicinal chemist's dream: Faster design of better and safer drug candidates

Successful drug research depends on adequate links between therapeutic benefits for the treatment of a disease, pertinent biological targets and suitable chemical compounds. The pharmacochemistry group at EPGL is active in the development of virtual and experimental methods to enhance these links following a general hit and lead generation strategy to reduce large chemically diverse databases to lead collections. This strategy is based on a careful definition of its numerous steps and on a series of key validation processes. Particular attention is devoted to identify and improve the usefulness of virtual screening techniques widely used in drug development. The guidelines proposed here to use the best validated tools in the most suitable order will help the medicinal chemist to approach his dream, namely to be faster in the design of better and safer drug candidate