Prioritisation of polybrominated diphenyl ethers (PBDEs) by using the QSPR-THESAURUS web tool.

The prioritisation of chemical compounds is important for the identification of those chemicals that represent the highest threat to the environment. As part of the CADASTER project (http: / /www.cadaster.eu), we developed an online web tool that allows the calculation of the environmental risk of chemical compounds from a web interface. The environmental fate of compounds in the aquatic compartment is assessed by using the SimpleBox model, while adverse effects on the aquatic compartment are assessed by the Species Sensitivity Distribution approach. The main purpose of this web tool is to exemplify the use of quantitative structure-activity relationships (QSARs) to support risk assessment. A case study of QSAR integrated risk assessment of 209 polybrominated diphenyl ethers (PBDEs) demonstrates the treatment and influence of uncertainty in the predicted physicochemical and toxicity parameters in probabilistic risk assessment.

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information.

The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self-administration II: phasic firing patterns.

In the cocaine self-administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self-administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13-17 of cocaine self-administration (0.77 mg/kg per 0.2-mL infusion; fixed-ratio 1 schedule of reinforcement; 6-h daily sessions). Pre-press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre-press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre-press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.

Applicability domains for classification problems: Benchmarking of distance to models for Ames mutagenicity set.

The estimation of accuracy and applicability of QSAR and QSPR models for biological and physicochemical properties represents a critical problem. The developed parameter of "distance to model" (DM) is defined as a metric of similarity between the training and test set compounds that have been subjected to QSAR/QSPR modeling. In our previous work, we demonstrated the utility and optimal performance of DM metrics that have been based on the standard deviation within an ensemble of QSAR models. The current study applies such analysis to 30 QSAR models for the Ames mutagenicity data set that were previously reported within the 2009 QSAR challenge. We demonstrate that the DMs based on an ensemble (consensus) model provide systematically better performance than other DMs. The presented approach identifies 30-60% of compounds having an accuracy of prediction similar to the interlaboratory accuracy of the Ames test, which is estimated to be 90%. Thus, the in silico predictions can be used to halve the cost of experimental measurements by providing a similar prediction accuracy. The developed model has been made publicly available at http://ochem.eu/models/1 .

Electrophysiological evidence of mediolateral functional dichotomy in the rat accumbens during cocaine self-administration: tonic firing patterns.

Given the increasing research emphasis on putative accumbal functional compartmentation, we sought to determine whether neurons that demonstrate changes in tonic firing rate during cocaine self-administration are differentially distributed across subregions of the NAcc. Rats were implanted with jugular catheters and microwire arrays targeting NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell and rostral pole shell). Recordings were obtained after acquisition of stable cocaine self-administration (0.77 mg/kg/0.2mL infusion; fixed-ratio 1 schedule of reinforcement; 6-h daily sessions). During the self-administration phase of the experiment, neurons demonstrated either: (i) tonic suppression (or decrease); (ii) tonic activation (or increase); or (iii) no tonic change in firing rate with respect to rates of firing during pre- and post-drug phases. Consistent with earlier observations, tonic decrease was the predominant firing pattern observed. Differences in the prevalence of tonic increase firing were observed between the core and the dorsal shell and dorsal shell-core border regions, with the latter two areas exhibiting a virtual absence of tonic increases. Tonic suppression was exhibited to a greater extent by the dorsal shell-core border region relative to the core. These differences could reflect distinct subregional afferent processing and/or differential sensitivity of subpopulations of NAcc neurons to cocaine. Ventrolateral shell firing topographies resembled those of core neurons. Taken together, these observations are consistent with an emerging body of literature that differentiates the accumbens mediolaterally and further advances the likelihood that distinct functions are subserved by NAcc subregions in appetitive processing.

Design, synthesis and evaluation of novel sulfonamides as potential anticancer agents.

Based on modern literature data about biological activity of E7010 derivatives, a series of new sulfonamides as potential anticancer drugs were rationally designed by QSAR modeling methods Сlassification learning QSAR models to predict the tubulin polymerization inhibition activity of novel sulfonamides as potential anticancer agents were created using the Online Chemical Modeling Environment (OCHEM) and are freely available online on OCHEM server at https://ochem.eu/article/107790. A series of sulfonamides with predicted activity were synthesized and tested against 60 human cancer cell lines with growth inhibition percent values. The highest antiproliferative activity against leukemia (cell lines K-562 and MOLT-4), non-small cell lung cancer (cell line NCI-H522), colon cancer (cell lines NT29 and SW-620), melanoma (cell lines MALME-3M and UACC-257), ovarian cancer (cell lines IGROV1 and OVCAR-3), renal cancer (cell lines ACHN and UO-31), breast cancer (cell line T-47D) was found for compounds 4-9. According to the docking results the compounds 4-9 induce cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, similar the E7010.

Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine.

Persistent neural processing of information regarding drug-predictive environmental stimuli may be involved in motivating drug abusers to engage in drug seeking after abstinence. The addictive effects of various drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens. We used single-unit recording in rats to test whether accumbens neurons exhibit responses to a discriminative stimulus (SD) tone previously paired with cocaine availability during cocaine self-administration. Presentation of the tone after 3-4 weeks of abstinence resulted in a cue-induced relapse of drug seeking under extinction conditions. Accumbens neurons did not exhibit tone-evoked activity before cocaine self-administration training but exhibited significant SD tone-evoked activity during extinction. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than that evoked by a neutral tone (i.e., never paired with reinforcement). In contrast, core neurons responded indiscriminately to presentations of the SD tone or the neutral tone. Accumbens shell neurons exhibited significantly greater SD tone-evoked activity than did accumbens core neurons. Although the onset of SD tone-evoked activity occurred well before the earliest movements commenced (150 msec), this activity often persisted beyond the onset of tone-evoked movements. These results indicate that accumbens shell neurons exhibit persistent processing of information regarding reward-related stimuli after prolonged drug abstinence. Moreover, the accumbens shell appears to be involved in discriminating the motivational value of reward-related associative stimuli, whereas the accumbens core does not.

Prediction of thrombin and factor xa inhibitory activity with associative neural networks.

Quantitative structure-activity relationship studies on a series of selective inhibitors of thrombin and factor Xa were performed by using Associative Neural Network. To overcome the problem of overfitting due to descriptor selection, 5-fold cross-validation with variable selection in each step of the analysis was performed. The predictive ability of the models was tested through leave-one-out cross-validation, giving a Q2=0.74-0.87 for regression models. Predictions for the external evaluation sets obtained accuracies in the range of 0.71-0.82 for regressions. The proposed models can be potential tools for finding new drug candidates.

Design and synthesis of new potent inhibitors of farnesyl pyrophosphate synthase.

Predictive QSAR models for the inhibition activities of nitrogen-containing bisphosphonates (N-BPs) against farnesyl pyrophosphate synthase (FPPS) from Leishmania major (LeFPPS) were developed using a data set of 97 compounds. The QSAR models were developed through the use of Artificial Neural Networks and Random Forest learning procedures. The predictive ability of the models was tested by means of leave-one-out cross-validation; Q(2)values ranging from 0.45-0.79 were obtained for the regression models. The consensus prediction for the external evaluation set afforded high predictive power (Q(2)=0.76 for 35 compounds). The robustness of the QSAR models was also evaluated using a Y-randomization procedure. A small set of 6 new N-BPs were designed and synthesized applying the Michael reaction of tetrakis (trimethylsilyl) ethenylidene bisphosphonate with amines. The inhibition activities of these compounds against LeFPPS were predicted by the developed QSAR models and were found to correlate with their fungistatic activities against Candida albicans. The antifungal activities of N-BPs bearing n-butyl and cyclopropyl side chains exceeded the activities of Fluconazole, a triazole-containing antifungal drug. In conclusion, the N-BPs developed here present promising candidate drugs for the treatment of fungal diseases.

Predictive QSAR modeling of phosphodiesterase 4 inhibitors.

A series of diverse organic compounds, phosphodiesterase type 4 (PDE-4) inhibitors, have been modeled using a QSAR-based approach. 48 QSAR models were compared by following the same procedure with different combinations of descriptors and machine learning methods. QSAR methodologies used random forests and associative neural networks. The predictive ability of the models was tested through leave-one-out cross-validation, giving a Q² = 0.66-0.78 for regression models and total accuracies Ac=0.85-0.91 for classification models. Predictions for the external evaluation sets obtained accuracies in the range of 0.82-0.88 (for active/inactive classifications) and Q² = 0.62-0.76 for regressions. The method showed itself to be a potential tool for estimation of IC50 of new drug-like candidates at early stages of drug development.

Changes in activity of the striatum during formation of a motor habit.

To examine experience-dependent plasticity of striatal neurons during habit learning in awake, freely moving animals, single neurons in the dorsolateral striatum (54 neurons related specifically to vertical head movement and 14 unresponsive neurons, i.e. not related to any body movement) were recorded and tracked off-line to assess changes in firing rate over sessions as performance of instrumental head movement became automatic and habitual. Rats were trained to emit operant vertical head movements that triggered water delivery for 14 sessions (2 h per session, one session per day). Rats significantly increased the number and efficiency of head movements over sessions until reaching asymptotic behaviour. Habit formation was indicated by significantly higher levels of instrumental responding exhibited by rats during a late, relative to an early, session in which the reward was devalued. As head movements became habitual across sessions, most head movement-related neurons (89%) exhibited decreased firing rate, while a small population (11%) exhibited increased or maintained firing rate. The rate of decrease in firing by the majority correlated with the rate of improvement in movement efficiency over sessions. All unresponsive neurons, though not apparently related to movement, exhibited decreased firing rate over sessions. Our findings suggest that, during habit learning, the striatum may shift from facilitating acquisition of efficient movement with a large population of neurons to modulating or maintaining habitual movement with stronger firing of fewer movement-related neurons.

Virtual computational chemistry laboratory--design and description.

Internet technology offers an excellent opportunity for the development of tools by the cooperative effort of various groups and institutions. We have developed a multi-platform software system, Virtual Computational Chemistry Laboratory, http://www.vcclab.org, allowing the computational chemist to perform a comprehensive series of molecular indices/properties calculations and data analysis. The implemented software is based on a three-tier architecture that is one of the standard technologies to provide client-server services on the Internet. The developed software includes several popular programs, including the indices generation program, DRAGON, a 3D structure generator, CORINA, a program to predict lipophilicity and aqueous solubility of chemicals, ALOGPS and others. All these programs are running at the host institutes located in five countries over Europe. In this article we review the main features and statistics of the developed system that can be used as a prototype for academic and industry models.

Differences between accumbens core and shell neurons exhibiting phasic firing patterns related to drug-seeking behavior during a discriminative-stimulus task.

The habit-forming effects of abused drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens (NAcc). To examine whether different NAcc subterritories (core and medial shell) exhibit a differential distribution of neurons showing phasic firing patterns correlated with drug-seeking behavior, rats were trained to self-administer cocaine, and activity of single NAcc neurons was recorded. In the presence of a discriminative-stimulus (S(D)) tone, a single lever press produced an intravenous infusion of cocaine (0.35 mg/kg), terminated the tone, and started an intertone interval ranging from 3 to 6 min. Lever presses during this intertone interval had no programmed consequences. In addition to evaluating neuronal firing patterns associated with cocaine-reinforced presses, we also evaluated firing patterns associated with unreinforced lever presses to allow interpretation of firing free of factors other than the instrumental response (such as tone-off and onset of the pump signaling drug infusion). Core neurons exhibited a greater change in firing than medial shell neurons both in the seconds preceding the reinforced and unreinforced lever press response and in the seconds following the unreinforced response. Core and medial shell neurons exhibited similar changes in firing during the seconds following the cocaine-reinforced press. The differential distribution of neurons exhibiting phasic changes in firing preceding the lever press suggests that the physiological activity of core neurons may play a greater role than that of medial shell neurons in processes related to the execution of conditioned drug-seeking responses.

A web portal for classification of expression data using maximal margin linear programming.

The Maximal Margin (MAMA) linear programming classification algorithm has recently been proposed and tested for cancer classification based on expression data. It demonstrated sound performance on publicly available expression datasets. We developed a web interface to allow potential users easy access to the MAMA classification tool. Basic and advanced options provide flexibility in exploitation. The input data format is the same as that used in most publicly available datasets. This makes the web resource particularly convenient for non-expert machine learning users working in the field of expression data analysis.