Конструирование методики исследования саморазвития личности

У статті розглядається авторський підхід до розробки діагностичного інструментарію вивчення особливостей саморозвитку особистості. Аналізуються змістові компоненти (психологічні ресурси) особистісного саморозвитку. Наводиться розроблена діагностична методика ДХСО. Описується процедура перевірки валідності і надійності, а також стандартизації результатів.In the article the author's approach to the development of diagnostic tools study features self-identity. Analyzed a substantial of components (psychological resources) personal self-development. A developed of diagnostic the technique DCSEP. A procedure of checking the validity and reliability, as well as standardization of results.В статье рассматривается авторский подход к разработке диагностического инструментария изучения особенностей саморазвития личности. Анализируются содержательные компоненты (психологические ресурсы) личностного саморазвития. Приводится разработанная диагностическая методика ДХСЛ. Описывается процедура проверки валидности и надежности, а также стандартизации результатов

From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action

Pharmacolog

Discovery of Protein-Protein Interaction Inhibitors by Integrating Protein Engineering and Chemical Screening Platforms

Protein-protein interactions (PPIs) govern intracellular life, and identification of PPI inhibitors is challenging. Roadblocks in assay development stemming from weak binding affinities of natural PPIs impede progress in this field. We postulated that enhancing binding affinity of natural PPIs via protein engineering will aid assay development and hit discovery. This proof-of-principle study targets PPI between linear ubiquitin chains and NEMO UBAN domain, which activates NF-κB signaling. Using phage display, we generated ubiquitin variants that bind to the functional UBAN epitope with high affinity, act as competitive inhibitors, and structurally maintain the existing PPI interface. When utilized in assay development, variants enable generation of robust cell-based assays for chemical screening. Top compounds identified using this approach directly bind to UBAN and dampen NF-κB signaling. This study illustrates advantages of integrating protein engineering and chemical screening in hit identification, a development that we anticipate will have wide application in drug discovery

Design, synthesis and antiparasitic evaluation of click phospholipids

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure\u2013activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 \ub5M. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases

ТЕКТОНОФИЗИЧЕСКИЕ ИССЛЕДОВАНИЯ АКТИВНОСТИ РАЗЛОМА ВЕРХОВОГО НА СЕВЕРНОМ СКЛОНЕ КИРГИЗСКОГО ХРЕБТА

An active fault was identified on the northern slope of the Kyrgyz ridge in the area near Research Scientific RAS in Bishkek. It belongs to a large system of crustal faults of the ridge. In our study, tectonophysical methods were used to analyse the regularities of the tectonic stress field reconstructed from seismological data on earthquake focal mechanisms. The stress distribution pattern near the investigated fault suggests its activity either in the recent past or at the present time. This conclusion is supported by the fact that at the eastern and western terminations of the fault, crustal stretching zones are located in a crosswise pattern. The Coulomb stresses on the fault surface were analysed, and the analysis results give grounds to state that its long section crossing the Alamedin river valley should be viewed as potentially hazardous. In the field, we observed abundant broken rock fragments and rock falls in the zone where the fault crosses the Alamedin and Aksu river valleys. It is known that rock falls have occurred more often in the last 3–5 years. The study results show slow movements along the fault. These strike-slip displacements have been going on for at least 10–15 years. According to the modern concepts of the preparation stage of an earthquake source, slow displacements along a fault gradually accelerate several years before an earthquake. Therefore, the studied fault (we named it Verkhovoi) should be considered a potentially hazardous zone wherein earthquakes can occur in future. A magnitude from 6.5 to 7.5 may be expected, depending on whether only the eastern part or the entire fault (i.e. 20 or 50 km, respectively) will be involved in a future seismic event. Further studies of the Verkhovoi fault are needed to clarify a trend in the development of slow sliding along the fault, which will allow understanding whether this process precedes dynamic rock failure (i.e. an earthquake) or tends to gradually decrease.Представлены результаты исследования активного разлома вблизи Научной станции РАН в г. Бишкеке. Выделение этого разлома из большой группы разломов для коры Киргизского хребта выполнено на основе тектонофизических методов анализа закономерности поля тектонических напряжений, полученного из сейсмологических данных о механизмах очагов землетрясений. Распределение напряжений вблизи исследованного безымянного разлома на северном склоне Киргизского хребта говорит о его активности либо в недавнем прошлом, либо в настоящее время. Этот вывод опирается на наличие в его восточном и западном окончании крестообразно расположенных секторов растяжения. Анализ кулоновых напряжений на поверхности разлома показал, что его протяженный участок, пересекающий долину р. Аламедин, следует рассматривать как потенциально опасный. Проведенные полевые геологические работы позволили установить, что в районе пересечения этим разломом долин Аламедин и Аксу происходит обильное образование каменных осыпей и вывалов, причем в последние 3–5 лет активность каменных вывалов возросла. На основе полученных данных мы предполагаем, что исследуемый разлом испытывает медленные движения (сдвиги по простиранию), которые продолжаются уже не менее 10–15 лет. Согласно современным представлениям о стадии подготовки очага землетрясения, за несколько лет до его реализации на разломе начинается медленное, постепенно ускоряющееся смещение, поэтому данный разлом следует рассматривать как потенциально опасный для будущего землетрясения. Ожидаемая магнитуда землетрясения от 6.5 до 7.5 и зависит от реализации восточной части или всего разлома протяженностью соответственно 20 и 50 км. Предполагается дальнейшее изучение этого разлома, названного нами «Верховой», с целью выяснения тенденции развития процесса медленного скольжения в динамический срыв – землетрясение или постепенное затухание скольжения

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit <i>Trypanosoma brucei </i>Pteridine Reductase in Support of Early-Stage Drug Discovery

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics