Конформація пропоксазепаму та його орієнтація у центрі зв’язування ГАМКА-рецептора

Introduction. One of 1.4-benzodiazepine 3-alcoxy derivatives – propoxazepam, possessing high analgetic action, also effectively suppressed different experimental seizures types. Unexpected combination of pharmacological spectrum components suggests its different binding sites of GABAA receptor.The aim of the work was to determine the geometry of the ligand-receptor complexes of GABA-RC using experimental data of the propoxazepam conformation and calculated data for the three-dimensional structure of the ligandbinding site and subsequent docking to characterize its binding to this receptor.Materials and methods. X-ray diffraction studies of the compound were performed using Xcalibur 3 single crystal X-ray diffractometer. Calculation of the molecular docking parameters was performed using the iGEMDOCK v2.1 program for the GABA receptor (GABA (A) R-beta3 homopentamer, 4COF), the molecular structures of propoxazepam conformers were prepared using ChemAxon (MarvinSketch 17.11.0).Results and discussion. Based on the X-ray diffraction analysis, the coordinates of the atoms, bond lengths and valence angles in the propoxazepam molecule were calculated, it is found that it form crystallographic twins as racemate. The molecular docking method showed that propoxazepam several binding sites with the energy of complex formation from -78.64 to -85.29 kcal/mol exist on the isolated site of the GABA-receptor.Conclusions. The highest contribution to the formation of the bond of the complex is carried out by residues of polar amino acids (serine, asparagine, methionine and arginine in polar binding sub-center). However, also for individual conformers, aromatic amino acids, predominantly phenylalanine (Phe-31, Ala-135 – hydrophobic binding sub-center) make a significant contribution.Актуальность. Одно из 3-алкоксипроизводных 1,4-бенздиазепина – пропоксазепам – продемонстрировал высокую анальгетическую активность, а также эффективно блокировал разные типы экспериментальных судорог. Нестандартная комбинация компонентов фармакологического спектра предусматривает разные места его связывания на ГАМКА-рецепторе.Цель исследования состояла в определении геометрии лигандрецепторных комплексов ГАМК-РК на основе использования экспериментальных данных о конформации пропоксазепама и расчетных данных о трехмерном строении лигандсвязывающего центра и последующее проведение докинга для характеристики его связывания с данным рецептором.Материалы и методы. Рентгеноструктурное исследование соединения выполнено на монокристальном рентгеновском дифрактометре Xcalibur 3, Расчет параметров молекулярного докинга был осуществлен с использованием программы iGEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 гомопентамер, 4COF), молекулярные структуры конформеров пропоксазепама были подготовлены в программе ChemAxon (MarvinSketch 17.11.0).                                                                                              Результаты и их обсуждение. На основании данных рентгеноструктурного анализа рассчитаны координаты атомов, длины связей и валентные углы в молекуле пропоксазепама, установлено, что он существует в виде кристаллографического двойника в виде рацемата.                                      Выводы. Методом молекулярного докинга показано, что на выделенном участке ГАМКА-рецептора существует несколько мест связывания пропоксазепама с энергией образования комплекса от -78,64 до -85,29 ккал/моль. Наибольший вклад в формирование связи комплекса осуществляют остатки полярных аминокислот (серин, аспарагин, метионин и аргинин – полярный подцентр связывания). Однако также для отдельных конформеров значительный вклад имеют ароматические аминокислоты, преимущественно фенилаланин (Phe-31, Ala-135 – гидрофобный подцентр связывания).Актуальність. Одне з 3-алкоксипохідних 1,4-бенздіазепіну – пропоксазепам, який продемонстрував високу аналгетичну активність, а також ефективно блокував різні типи експериментальних судом. Нестандартна комбінація компонентів фармакологічного спектра передбачає різні місця його зв’язування на ГАМКА-рецепторі.Мета дослідження полягала у визначенні геометрії ліганд-рецепторних комплексів ГАМК-РК на підставі використання експериментальних даних про конформацію пропоксазепаму та розрахункових даних тривимірної будови лігандзв’язуючого центра та подальше проведення докінгу для характеристики його зв’язування з даним рецептором.Матеріали та методи. Рентгеноструктурне дослідження сполуки було виконано на монокристальному рентгенівському дифрактометрі Xcalibur 3, розрахунок параметрів молекулярного докінгу буз здійснений у програмі GEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 пентамер); молекулярні структури конформерів пропоксазепаму були підготовлені у програмі ChemAxon (MarvinSketch 17.11.0).Результати та їх обговорення. На підставі даних рентгеноструктурного аналізу розраховані координати атомів, довжини зв’язків та валентні кути у молекулі пропоксазепаму, встановлено, що він існує у вигляді кристалографічного двійника як рацемат.Висновки. Методом молекулярного докінгу показано, що на виділеній частині ГАМКА-рецептора існує декілька місць зв’язування пропоксазепаму з енергією утворення комплексів від -78,64 до -85,29 ккал/моль. Найбільший внесок у формування зв’язку комплексу здійснюють залишки полярних амінокислот (серин, аспарагін, метіонін та аргінін – полярний підцентр зв’язування). Однак також для окремих конформерів значний внесок мають ароматичні амінокислоти, переважно фенілаланін (Phe-31, Ala-135 – гідрофобний підцентр зв’язування)

Evidence for T Tauri-like emission in the EXor V1118 Ori from near-IR and X-ray data

We present a near-IR study of the EXor variable V1118 Ori, performed by following a slightly declining phase after a recent outburst. In particular, the near-IR (0.8 - 2.3 micron) spectrum, obtained for the first time, shows a large variety of emission features of the HI and HeI recombination and CO overtone. By comparing the observed spectrum with a wind model, a mass loss rate value is derived along with other parameters whose values are typical of an accreting T Tauri star. In addition, we have used X-ray data from the XMM archive, taken in two different epochs during the declining phase monitored in IR. X-ray emission (in the range 0.5 - 10 keV) permits to derive several parameters which confirm the T Tauri nature of the source. In the near-IR the object maintains a low visual extinction during all the activity phases, confirming that variable extinction does not contribute to brightness variations. The lack of both a significant amount of circumstellar material and any evidence of IR cooling from collimated jet/outflow driven by the source, indicates that, at least this member of the EXor class, is in a late stage of the Pre-Main Sequence evolution. In the X-ray regime, an evident fading is present, detected in the post-outburst phase, that cannot be reconciled with the presence of any absorbing material. This circumstance, combined with the persistence (in the pre- and post-outburst phases) of a temperature component at about 10 MK, suggests that accretion has some influence in regulating the coronal activity

Strongly damped nuclear collisions: zero or first sound ?

The relaxation of the collective quadrupole motion in the initial stage of a central heavy ion collision at beam energies $E_{lab}=5\div20$ AMeV is studied within a microscopic kinetic transport model. The damping rate is shown to be a non-monotonic function of E_{lab} for a given pair of colliding nuclei. This fact is interpreted as a manifestation of the zero-to-first sound transition in a finite nuclear system.Comment: 15 pages, 4 figure

Isovector Collective Response Function of Nuclear Matter at Finite Temperature

We study isovector collective excitations in nuclear matter by employing the linearized Landau-Vlasov equation with and without a non-Markovian binary collision term at finite temperature. We calculate the giant dipole resonance (GDR) strength function for finite nuclei using Steinwedel-Jensen model and also by Thomas-Fermi approximation, and we compare them for 120Sn and 208Pb with experimental results.Comment: 15 pages, 4 figure

Simultaneous monitoring of the photometric and polarimetric activity of the young star PV Cep in the optical/near-infrared bands

We present the results of a simultaneous monitoring, lasting more than 2 years, of the optical and near-infrared photometric and polarimetric activity of the variable protostar PV Cep. During the monitoring period, an outburst has occurred in all the photometric bands, whose declining phase ($\Delta$J $\approx$ 3 mag) lasted about 120 days. A time lag of $\sim$ 30 days between optical and infrared light curves has been measured and interpreted in the framework of an accretion event. This latter is directly recognizable in the significant variations of the near-infrared colors, that appear bluer in the outburst phase, when the star dominates the emission, and redder in declining phase, when the disk emission prevails. All the observational data have been combined to derive a coherent picture of the complex morphology of the whole PV Cep system, that, in addition to the star and the accretion disk, is composed also by a variable biconical nebula. In particular, the mutual interaction between all these components is the cause of the high value of the polarization ($\approx$ 20%) and of its fluctuations. The observational data concur to indicate that PV Cep is not a genuine EXor star, but rather a more complex object; moreover the case of PV Cep leads to argue about the classification of other recently discovered young sources in outburst, that have been considered, maybe over-simplifying, as EXor.Comment: Accepted for publication on Ap

A long-lasting quiescence phase of the eruptive variable V1118 Ori

V1118 Ori is an eruptive variable belonging to the EXor class of Pre-Main Sequence stars whose episodic outbursts are attributed to disk accretion events. Since 2006, V1118 Ori is in the longest quiescence stage ever observed between two subsequent outbursts of its recent history. We present near-infrared photometry of V1118 Ori carried out during the last eight years, along with a complete spectroscopic coverage from 0.35 to 2.5 um. A longterm sampling of V1118 Ori in quiescence has never been done, hence we can benefit from the current circumstance to determine the lowest values (i.e. the zeroes) of the parameters to be used as a reference for evaluating the physical changes typical of more active phases. A quiescence mass accretion rate between 1--3 $\times$ 10$^{-9}$ M_{\sun} yr$^{-1}$ can be derived and the difference with previous determinations is discussed. From line emission and IR colors analysis a visual extinction of 1-2 mag is consistently derived, confirming that V1118 Ori (at least in quiescence) is a low-extinction T Tauri star with a bolometric luminosity of about 2.1 L_{\sun}. An anti-correlation exists between the equivalent width of the emission lines and the underlying continuum. We searched the literature for evaluating whether or not such a behaviour is a common feature of the whole class. The anti-correlation is clearly recognizable for all the available EXors in the optical range (H$\beta$ and H$\alpha$ lines), while it is not as much evident in the infrared (Pa$\beta$ and Br$\gamma$ lines). The observed anti-correlation supports the accretion-driven mechanism as the most likely to account for continuum variations.Comment: 6 figures, 5 tables, accepted on Ap