Dataset Information

Performance of Machine Learning Algorithms for Qualitative and Quantitative Prediction Drug Blockade of hERG1 channel.

ABSTRACT: Drug-induced abnormal heart rhythm known as Torsades de Pointes (TdP) is a potential lethal ventricular tachycardia found in many patients. Even newly released anti-arrhythmic drugs, like ivabradine with HCN channel as a primary target, block the hERG potassium current in overlapping concentration interval. Promiscuous drug block to hERG channel may potentially lead to perturbation of the action potential duration (APD) and TdP, especially when with combined with polypharmacy and/or electrolyte disturbances. The example of novel anti-arrhythmic ivabradine illustrates clinically important and ongoing deficit in drug design and warrants for better screening methods. There is an urgent need to develop new approaches for rapid and accurate assessment of how drugs with complex interactions and multiple subcellular targets can predispose or protect from drug-induced TdP. One of the unexpected outcomes of compulsory hERG screening implemented in USA and European Union resulted in large datasets of IC50 values for various molecules entering the market. The abundant data allows now to construct predictive machine-learning (ML) models. Novel ML algorithms and techniques promise better accuracy in determining IC50 values of hERG blockade that is comparable or surpassing that of the earlier QSAR or molecular modeling technique. To test the performance of modern ML techniques, we have developed a computational platform integrating various workflows for quantitative structure activity relationship (QSAR) models using data from the ChEMBL database. To establish predictive powers of ML-based algorithms we computed IC50 values for large dataset of molecules and compared it to automated patch clamp system for a large dataset of hERG blocking and non-blocking drugs, an industry gold standard in studies of cardiotoxicity. The optimal protocol with high sensitivity and predictive power is based on the novel eXtreme gradient boosting (XGBoost) algorithm. The ML-platform with XGBoost displays excellent performance with a coefficient of determination of up to R2 ~0.8 for pIC50 values in evaluation datasets, surpassing other metrics and approaches available in literature. Ultimately, the ML-based platform developed in our work is a scalable framework with automation potential to interact with other developing technologies in cardiotoxicity field, including high-throughput electrophysiology measurements delivering large datasets of profiled drugs, rapid synthesis and drug development via progress in synthetic biology.

SUBMITTER: Wacker S

PROVIDER: S-EPMC5967266 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Performance of Machine Learning Algorithms for Qualitative and Quantitative Prediction Drug Blockade of hERG1 channel.

Wacker Soren S Noskov Sergei Yu SY

Computational toxicology (Amsterdam, Netherlands) 20170513

Drug-induced abnormal heart rhythm known as <i>Torsades de Pointes</i> (TdP) is a potential lethal ventricular tachycardia found in many patients. Even newly released anti-arrhythmic drugs, like ivabradine with HCN channel as a primary target, block the hERG potassium current in overlapping concentration interval. Promiscuous drug block to hERG channel may potentially lead to perturbation of the action potential duration (APD) and TdP, especially when with combined with polypharmacy and/or elect ...[more]

PMID: 29806042

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Project description:Drug-induced cardiotoxicity is a potentially lethal and yet one of the most common side effects with the drugs in clinical use. Most of the drug-induced cardiotoxicity is associated with an off-target pharmacological blockade of K+ currents carried out by the cardiac Human-Ether-a-go-go-Related (hERG1) potassium channel. There is a compulsory preclinical stage safety assessment for the hERG1 blockade for all classes of drugs, which adds substantially to the cost of drug development. The availability of a high-resolution cryogenic electron microscopy (cryo-EM) structure for the channel in its open/depolarized state solved in 2017 enabled the application of molecular modeling for rapid assessment of drug blockade by molecular docking and simulation techniques. More importantly, if successful, in silico methods may allow a path to lead-compound salvaging by mapping out key block determinants. Here, we report the blind application of the site identification by the ligand competitive saturation (SILCS) protocol to map out druggable/regulatory hotspots in the hERG1 channel available for blockers and activators. The SILCS simulations use small solutes representative of common functional groups to sample the chemical space for the entire protein and its environment using all-atom simulations. The resulting chemical maps, FragMaps, explicitly account for receptor flexibility, protein-fragment interactions, and fragment desolvation penalty allowing for rapid ranking of potential ligands as blockers or nonblockers of hERG1. To illustrate the power of the approach, SILCS was applied to a test set of 55 blockers with diverse chemical scaffolds and pIC50 values measured under uniform conditions. The original SILCS model was based on the all-atom modeling of the hERG1 channel in an explicit lipid bilayer and was further augmented with a Bayesian-optimization/machine-learning (BML) stage employing an independent literature-derived training set of 163 molecules. BML approach was used to determine weighting factors for the FragMaps contributions to the scoring function. pIC50 predictions from the combined SILCS/BML approach to the 55 blockers showed a Pearson correlation (PC) coefficient of >0.535 relative to the experimental data. SILCS/BML model was shown to yield substantially improved performance as compared to commonly used rigid and flexible molecular docking methods for a well-established cohort of hERG1 blockers, where no correlation with experimental data was recorded. SILCS/BML results also suggest that a proper weighting of protonation states of common blockers present at physiological pH is essential for accurate predictions of blocker potency. The precalculated and optimized SILCS FragMaps can now be used for the rapid screening of small molecules for their cardiotoxic potential as well as for exploring alternative binding pockets in the hERG1 channel with applications to the rational design of activators.

Project description:Cyber-attacks have become one of the biggest problems of the world. They cause serious financial damages to countries and people every day. The increase in cyber-attacks also brings along cyber-crime. The key factors in the fight against crime and criminals are identifying the perpetrators of cyber-crime and understanding the methods of attack. Detecting and avoiding cyber-attacks are difficult tasks. However, researchers have recently been solving these problems by developing security models and making predictions through artificial intelligence methods. A high number of methods of crime prediction are available in the literature. On the other hand, they suffer from a deficiency in predicting cyber-crime and cyber-attack methods. This problem can be tackled by identifying an attack and the perpetrator of such attack, using actual data. The data include the type of crime, gender of perpetrator, damage and methods of attack. The data can be acquired from the applications of the persons who were exposed to cyber-attacks to the forensic units. In this paper, we analyze cyber-crimes in two different models with machine-learning methods and predict the effect of the defined features on the detection of the cyber-attack method and the perpetrator. We used eight machine-learning methods in our approach and concluded that their accuracy ratios were close. The Support Vector Machine Linear was found out to be the most successful in the cyber-attack method, with an accuracy rate of 95.02%. In the first model, we could predict the types of attacks that the victims were likely to be exposed to with a high accuracy. The Logistic Regression was the leading method in detecting attackers with an accuracy rate of 65.42%. In the second model, we predicted whether the perpetrators could be identified by comparing their characteristics. Our results have revealed that the probability of cyber-attack decreases as the education and income level of victim increases. We believe that cyber-crime units will use the proposed model. It will also facilitate the detection of cyber-attacks and make the fight against these attacks easier and more effective.

Dataset Information

Performance of Machine Learning Algorithms for Qualitative and Quantitative Prediction Drug Blockade of hERG1 channel.

Publications

Performance of Machine Learning Algorithms for Qualitative and Quantitative Prediction Drug Blockade of hERG1 channel.

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