A new ligand-based method for the prediction of sites of metabolism (SOMs) for xenobiotics has been developed on the basis of the LMNA (labeled multilevel neighborhoods of atom) descriptors and the PASS (prediction of activity spectra for...

A new ligand-based method for the prediction of sites of metabolism (SOMs) for xenobiotics has been developed on the basis of the LMNA (labeled multilevel neighborhoods of atom) descriptors and the PASS (prediction of activity spectra for substances) algorithm and applied to predict the SOMs of the 1A2, 2C9, 2C19, 2D6, and 3A4 isoforms of cytochrome P450. An average IAP (invariant accuracy of prediction) of SOMs calculated by the leave-one out cross-validation procedure was 0.89 for the developed method. The external validation was made with evaluation sets containing data on biotransformations for 57 cardiovascular drugs. An average IAP of regioselectivity for evaluation sets was 0.83. It was shown that the proposed method exceeds accuracy of SOM prediction by RS-Predictor for CYP 1A2, 2D6, 2C9, 2C19, and 3A4 and is comparable to or better than SMARTCyp for CYP 2C9 and 2D6.
Journal of Chemical Information and Modeling, 2014, 54 (2), 498–507.

The search for new substances for the treatment and prophylaxis of HIV-AIDS remains relevant despite advances in highly active antiretroviral therapy (HAART), both because of the appearance of resistance to existing agents and because of their...

The search for new substances for the treatment and prophylaxis of HIV-AIDS remains relevant despite advances in highly active antiretroviral therapy (HAART), both because of the appearance of resistance to existing agents and because of their side effects and toxicity. Preventing the spread of HIV infection via sexual contacts by treating the uninfected partner has some advantage, as prophylactic effects can be obtained using simpler treatment (for example, using one agent rather than combinations of three drugs), as the need is to block the transfer of small numbers of infective virions. On the other hand, agents acting on the uninfected partner must be relatively nontoxic as they have to be used for long periods of time in healthy people. Effective chemoprophylaxis can be obtained using agents blocking the life cycle of the virus before integration into the human genome. Two widely used classes of agent therefore have potential – non-nucleoside reverse transcriptase (RT) inhibitors and integrase (IN) strand transfer inhibitors. In addition, proteins such as CD4, gp120, CCR5, CXCR4, and gp41 can be regarded as potential targets, as their functional roles at different stages in the interaction between virion and host cell have been established. As it is now known that all antiretroviral agents approved for medical use induce resistant viral strains, new anti-HIV agents must have chemical structures which are significantly different from known drugs and (if possible) must act on multiple pharmacological targets. Candidates can be sought by virtual screening of libraries of commercially available samples of chemical compounds; such libraries currently contain several million structural formulas for compounds which have been synthesized and are available for biological testing. Virtual screening can be performed using the computer programs PASS and PharmaExpert, allowing identification of substances with potential for experimental studies on the basis of a number of prognostic criteria (presence of the required types of activity, absence of side and toxic effects, appropriate physicochemical properties).We present here data on the current state of the search for new agents for the treatment and prophylaxis of HIV/AIDS, our approach to virtual screening for new potential substances for the prophylaxis of HIV/AIDS, and the results of using this approach in databases of chemical compounds available for screening. The potential for detection of anti-HIV compounds acting on multiple pharmacological targets among substances which have already been synthesized is discussed. We conclude that there is potential for the rational design of such drugs using computer-aided drug design methods.
Pharmaceutical Chemistry Journal, 2013, 47 (7), 343-360.

Поиск новых средств для лечения и профилактики ВИЧ/СПИД остается актуальным, несмотря на достижения высокоактивной...

Поиск новых средств для лечения и профилактики ВИЧ/СПИД остается актуальным, несмотря на достижения высокоактивной антиретровирусной терапии (ВААРТ), как из-за возникновения резистентности к существующим препаратам, так и из-за присущих им побочных эффектов и токсичности. Эффективная химиопрофилактика может быть достигнута путем применения препаратов, которые блокируют жизненный цикл вируса до того, как вирус интегрируется в геном человека. Поэтому преимуществами обладают два широко используемых класса препаратов – ненуклеозидные ингибиторы обратной транскриптазы (RT) и ингибиторы реакции переноса цепи интегразой (IN). Кроме того, в качестве перспективных мишеней могут рассматриваться такие белки, как CD4, gp120, CCR5, CXCR4 и gp41, так как установлена их функциональная роль на ранних стадиях взаимодействия вириона с клеткой хозяина. Поскольку к настоящему моменту установлено, что все разрешенные к медицинскому применению антиретровирусные препараты вызывают возникновение резистентных штаммов вируса, новые анти-ВИЧ вещества должны иметь существенные отличия по химической структуре от известных лекарств, а также (по возможности) воздействовать на несколько фармакологических мишеней. Поиск такого рода «кандидатов» может быть выполнен методами виртуального скрининга в библиотеках коммерчески доступных образцов химических соединений, которые в настоящее время содержат десятки миллионов структурных формул уже синтезированных и доступных для биологического тестирования веществ. Виртуальный скрининг может быть реализован путем применения компьютерных программ PASS и PharmaExpert, что позволяет отобрать вещества, перспективные для экспериментальных исследований с учетом ряда прогностических критериев (наличие требуемых видов активности, отсутствие побочных и токсических эффектов, необходимые физико-химические характеристики). В работе представлены: современное состояние поиска новых препаратов для терапии и профилактики ВИЧ/СПИД, разработанный нами подход к виртуальному скринингу новых потенциальных средств для профилактики ВИЧ/СПИД, и результаты ее применения к базам данных доступных для скрининга химических соединений. Проанализированы возможности выявления анти-ВИЧ препаратов, действующих на несколько фармакологических мишеней, среди уже синтезированных веществ. Сделан вывод о перспективности рационального дизайна таких лекарств путем применения методов компьютерного конструирования лекарств.
Химико-фармацевтический журнал, 2013, 47 (7) 3-21.

The (Q)SAR models for evaluating the structure–property relationships, fi t for prediction of drug interactions with P-glycoprotein as inhibitors or substrates, were constructed using PASS and GUSAR software. The models were constructed and...

The (Q)SAR models for evaluating the structure–property relationships, fi t for prediction of drug interactions with P-glycoprotein as inhibitors or substrates, were constructed using PASS and GUSAR software. The models were constructed and validated on the basis of information on the structure and characteristics of 256 and 94 compounds used as P-glycoprotein substrates and inhibitors, respectively. The initial samples were divided 80:20 into training and test samples. The best prediction accuracy for the test samples was 78% for P-glycoprotein substrate prediction (PASS) and 89% for inhibitor prediction (GUSAR).
Bulletin of Experimental Biology and Medicine, 2013, 154 (4), 521-524.

The problem of assessing the biological activity of organic xenobiotics using calculations like «structure – activity» is considered. This issue arises due to the fact that the number of anthropogenic and natural xenobiotics in environment...

The problem of assessing the biological activity of organic xenobiotics using calculations like «structure – activity» is considered. This issue arises due to the fact that the number of anthropogenic and natural xenobiotics in environment exceed the maximum allowable concentrations. Examples of such calculations for xenobiotics detected in water bodies illustrate the practical solution of the problem.
Water: Chemistry and Ecology, 2012, No. 1, p.3-12.

Р-гликопротеин (Pgp) является одним из основных АВС-транспортеров гематоэнцефалического барьера, осуществляющих выведение из мозга в...

Р-гликопротеин (Pgp) является одним из основных АВС-транспортеров гематоэнцефалического барьера, осуществляющих выведение из мозга в кровоток различных органических соединений, включая лекарства. Поэтому при создании новых лекарственных препаратов, необходимо учитывать их взаимодействие с Pgp в качестве субстратов или ингибиторов. C использованием компьютерных программ PASS и GUSAR мы построили (Q)SAR модели для оценки взаимосвязей «структура–свойство». При построении и валидации моделей была использована информация о структуре и свойствах 256 и 94 соединений, исследованных в качестве субстратов и ингибиторов Р-гликопротеина. Исходные выборки были разделены на обучающую и тестовую в пропорции 80:20. Лучшая точность предсказания, полученная для тестовых выборок, составила 78% при прогнозе субстратов (PASS) и 89% при прогнозе ингибиторов (GUSAR) Pgp.
Бюллетень экспериментальной биологии и медицины, 2012, 154 (10), 520-524.

Fragment-based drug design integrates different methods to create novel ligands using fragment libraries focused on the particular biological activities. Experimental approaches to fragment libraries preparation have some drawbacks caused by...

Fragment-based drug design integrates different methods to create novel ligands using fragment libraries focused on the particular biological activities. Experimental approaches to fragment libraries preparation have some drawbacks caused by necessity of target crystallization (X-ray and NMR) and careful immobilization (SPR). Molecular modeling (docking) requires accurate data on protein-ligand interactions, which are difficult to obtain for some proteins. The main drawbacks of QSAR application are associated with the need to collect large homogeneous datasets of chemical structures with experimentally determined self-consistent quantitative values (potency). We propose the ligand-based approach to the selection of fragments with positive contribution to the biological activity, developed on the basis of the PASS algorithm. The robustness of PASS algorithm for heterogeneous datasets has been shown earlier. PASS estimates qualitative (“yes”/”no”) prediction of biological activity spectra for over 4000 biological activities and, therefore, provides the basis for preparation of fragment library corresponding to multiple criteria. Algorithm of fragments selection has been validated using the fractions of intermolecular interactions calculated for known inhibitors of nine enzymes extracted from PDB. The statistical significance of differences between fractions of intermolecular interactions corresponds, for several enzymes, to the estimated positive and negative contribution of fragments into the enzyme inhibition.
SAR & QSAR Environ. Res., 2012, ., 23 (3-4), 279-296

Computer program PASS (Prediction of Activity Spectra for Substances) is described. Description of chemical structures, presetation of biological activity, mathematical method, training set, validation and applications are presented.

Computer program PASS (Prediction of Activity Spectra for Substances) is described. Description of chemical structures, presetation of biological activity, mathematical method, training set, validation and applications are presented.
In: Predictive Toxicology. Ed. by Christoph Helma. Taylor & Francis, 2005, pp.459-478.

На основе прогнозируемых с помощью компьютерной программы PASS спектров биологической активности было отобрано несколько...

На основе прогнозируемых с помощью компьютерной программы PASS спектров биологической активности было отобрано несколько антигипертензивных препаратов из группы ингибиторов АПФ для экспериментальной оценки ноотропной активности. Эксперименты проведены на мышах по тесту спонтанной ориентации (поведения патрулирования) в крестообразном лабиринте. В результате проведенных экспериментов обнаружено, что периндоприл в дозе 1 мг/кг, а квинаприл и моноприл в дозе 10 мг/кг вызывают улучшение показателей поведения патрулирования лабиринта. Данный эффект имеет сходство с эффектами эталонных ноотропных препаратов пирацетам и меклофеноксат (в дозах 300 и 120 мг/кг соответственно). Обнаруженное нами ноотропное действие некоторых ингибиторов АПФ, скорее всего, не связано с их антигипертензивным эффектом, поскольку ноотропное действие имело место лишь при относительно малых дозах периндоприла, квинаприла и моноприла и исчезало при дальнейшем увеличении дозы. Выявление ноотропных свойств у широко применяемых в медицинской практике антигипертензивных препаратов открывает возможности для их новых клинических применений с учетом соответствующих индивидуальных особенностей пациентов.
Хим.-фарм. журн., 2011, 45 (10), 25-31.

The method for QSAR modelling of rat acute toxicity based on the combination of QNA (Quantitative Neighbourhoods of Atoms) descriptors, PASS (Prediction of Activity Spectra for Substances) predictions and self-consistent regression (SCR) is...

The method for QSAR modelling of rat acute toxicity based on the combination of QNA (Quantitative Neighbourhoods of Atoms) descriptors, PASS (Prediction of Activity Spectra for Substances) predictions and self-consistent regression (SCR) is presented. PASS predicted biological activity profiles are used as independent input variables for QSAR modelling with SCR. QSAR models were developed using LD50 values for compounds tested on rats with four types of administration (oral, intravenous, intraperitoneal, subcutaneous). The proposed method was evaluated on the set of compounds tested for acute rat toxicity with oral administration (7286 compounds) used for testing the known QSAR methods in T.E.S.T. 3.0 program (U.S. EPA). The several other sets of compounds tested for acute rat toxicity by different routes of administration selected from SYMYX MDL Toxicity Database were used too. The method was compared with the results of prediction of acute rodent toxicity for noncongeneric sets obtained by ACD/Labs Inc. The test sets were predicted with regards to the applicability domain. Comparison of accuracy for QSAR models obtained separately using QNA descriptors, PASS predictions, nearest neighbours’ assessment with consensus models clearly demonstrated the benefits of consensus prediction. Free available web-service for prediction of LD50 values of rat acute toxicity was developed: http://www.pharmaexpert.ru/GUSAR/AcuToxPredict/
Molecular Informatics, 2011, 30 (2-3), 241–250.