Web Service for HIV Drug Resistance Prediction Based on Analysis of Amino Acid Substitutions in Main Drug Targets.

Predicting viral drug resistance is a significant medical concern. The importance of this problem stimulates the continuous development of experimental and new computational approaches. The use of computational approaches allows researchers to increase therapy effectiveness and reduce the time and expenses involved when the prescribed antiretroviral therapy is ineffective in the treatment of infection caused by the human immunodeficiency virus type 1 (HIV-1). We propose two machine learning methods and the appropriate models for predicting HIV drug resistance related to amino acid substitutions in HIV targets: (i) k-mers utilizing the random forest and the support vector machine algorithms of the scikit-learn library, and (ii) multi-n-grams using the Bayesian approach implemented in MultiPASSR software. Both multi-n-grams and k-mers were computed based on the amino acid sequences of HIV enzymes: reverse transcriptase and protease. The performance of the models was estimated by five-fold cross-validation. The resulting classification models have a relatively high reliability (minimum accuracy for the drugs is 0.82, maximum: 0.94) and were used to create a web application, HVR (HIV drug Resistance), for the prediction of HIV drug resistance to protease inhibitors and nucleoside and non-nucleoside reverse transcriptase inhibitors based on the analysis of the amino acid sequences of the appropriate HIV proteins from clinical samples.

In Silico Prediction of Drug-Drug Interactions Mediated by Cytochrome P450 Isoforms.

Drug-drug interactions (DDIs) can cause drug toxicities, reduced pharmacological effects, and adverse drug reactions. Studies aiming to determine the possible DDIs for an investigational drug are part of the drug discovery and development process and include an assessment of the DDIs potential mediated by inhibition or induction of the most important drug-metabolizing cytochrome P450 isoforms. Our study was dedicated to creating a computer model for prediction of the DDIs mediated by the seven most important P450 cytochromes: CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. For the creation of structure-activity relationship (SAR) models that predict metabolism-mediated DDIs for pairs of molecules, we applied the Prediction of Activity Spectra for Substances (PASS) software and Pairs of Substances Multilevel Neighborhoods of Atoms (PoSMNA) descriptors calculated based on structural formulas. About 2500 records on DDIs mediated by these cytochromes were used as a training set. Prediction can be carried out both for known drugs and for new, not-yet-synthesized substances. The average accuracy of the prediction of DDIs mediated by various isoforms of cytochrome P450 estimated by leave-one-out cross-validation (LOO CV) procedures was about 0.92. The SAR models created are publicly available as a web resource and provide predictions of DDIs mediated by the most important cytochromes P450.

Extraction of Data on Parent Compounds and Their Metabolites from Texts of Scientific Abstracts.

The growing amount of experimental data on chemical objects includes properties of small molecules, results of studies of their interaction with human and animal proteins, and methods of synthesis of organic compounds (OCs). The data obtained can be used to identify the names of OCs automatically, including all possible synonyms and relevant data on the molecular properties and biological activity. Utilization of different synonymic names of chemical compounds allows researchers to increase the completeness of data on their properties available from publications. Enrichment of the data on the names of chemical compounds by information about their possible metabolites can help estimate the biological effects of parent compounds and their metabolites more thoroughly. Therefore, an attempt at automated extraction of the names of parent compounds and their metabolites from the texts is a rather important task. In our study, we aimed at developing a method that provides the extraction of the named entities (NEs) of parent compounds and their metabolites from abstracts of scientific publications. Based on the application of the conditional random fields' algorithm, we extracted the NEs of chemical compounds. We developed a set of rules allowing identification of parent compound NEs and their metabolites in the texts. We evaluated the possibility of extracting the names of potential metabolites based on cosine similarity between strings representing names of parent compounds and all other chemical NEs found in the text. Additionally, we used conditional random fields to fetch the names of parent compounds and their metabolites from the texts based on the corpus of texts labeled manually. Our computational experiments showed that usage of rules in combination with cosine similarity could increase the accuracy of recognition of the names of metabolites compared to the rule-based algorithm and application of a machine-learning algorithm (conditional random fields).

Computer-Aided Estimation of Biological Activity Profiles of Drug-Like Compounds Taking into Account Their Metabolism in Human Body.

Most pharmaceutical substances interact with several or even many molecular targets in the organism, determining the complex profiles of their biological activity. Moreover, due to biotransformation in the human body, they form one or several metabolites with different biological activity profiles. Therefore, the development and rational use of novel drugs requires the analysis of their biological activity profiles, taking into account metabolism in the human body. In silico methods are currently widely used for estimating new drug-like compounds' interactions with pharmacological targets and predicting their metabolic transformations. In this study, we consider the estimation of the biological activity profiles of organic compounds, taking into account the action of both the parent molecule and its metabolites in the human body. We used an external dataset that consists of 864 parent compounds with known metabolites. It is shown that the complex assessment of active pharmaceutical ingredients' interactions with the human organism increases the quality of computer-aided estimates. The toxic and adverse effects showed the most significant difference: reaching 0.16 for recall and 0.14 for precision.

Chemo- and bioinformatics resources for in silico drug discovery from medicinal plants beyond their traditional use: a critical review.

In silico approaches have been widely recognised to be useful for drug discovery. Here, we consider the significance of available databases of medicinal plants and chemo- and bioinformatics tools for in silico drug discovery beyond the traditional use of folk medicines. This review contains a practical example of the application of combined chemo- and bioinformatics methods to study pleiotropic therapeutic effects (known and novel) of 50 medicinal plants from Traditional Indian Medicine.