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

Pharmacolog

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

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

X ray screening identifies active site and allosteric inhibitors of SARS CoV 2 main protease

The coronavirus disease COVID 19 caused by SARS CoV 2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID 19, we have performed a high throughput x ray crystallographic screen of two repurposing drug libraries against the SARS CoV 2 main protease Mpro , which is essential for viral 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 that bind to Mpro. In subsequent cell based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS CoV

Study of Ka-Band High-Power Transmission Lines

Analysis is presented of several high‐power transmission lines designed and built for use with a future normal‐conducting high‐energy collider. The transmission lines contain a number of components such as mode converters, bends, windows, combiners‐splitters, pumping ports, and compensators. Designs of these components take into account efficiency, reliability, and compactness. Low‐power tests of key components, as well as recent high‐power tests carried out in CERN, are described