Computational investigations on the binding mode of ligands for the cannabinoid-activated G protein-coupled receptor GPR18

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist A9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target

Glare Reducing Windscreen Using Principle of Selective Reflection

ABSTRACT:Automobiles are prone to accidents due to glare effect at night. The scope of this research is to reduce the glare. Theconcept of Electrochromic glass was used. A windscreen was made up of a pair of float glass enclosed with Twisted Nematic Liquid Crystals. The liquid crystal material exhibited a property of selective reflection of incident light. A liquid crystal material E48 was used for this purpose and the results were studied. The wavelength of light within a narrow range which caused glare was selectively reflected. This resulted in reduced intensity of glare thus protecting the driver from glare during night travel

Absence of extended atmospheres in low-mass star radius-gap planets GJ 9827 b, GJ 9827 d and TOI-1235 b

\textit{Kepler} showed a paucity of planets with radii of 1.5 - 2 $\mathrm R_{\oplus}$ around solar mass stars but this radius-gap has not been well studied for low-mass star planets. Energy-driven escape models like photoevaporation and core-powered mass-loss predict opposing transition regimes between rocky and non-rocky planets when compared to models depicting planets forming in gas-poor environments. Here we present transit observations of three super-Earth sized planets in the radius-gap around low-mass stars using high-dispersion InfraRed Doppler (IRD) spectrograph on the Subaru 8.2m telescope. The planets GJ 9827 b and d orbit around a K6V star and TOI-1235 b orbits a M0.5 star. We limit any planet-related absorption in the 1083.3 nm lines of triplet He I by placing an upper-limit on the equivalent width of 14.71 m{\AA}, 18.39 m{\AA}, and 1.44 m{\AA}, for GJ 9827 b (99% confidence), GJ 9827 d (99% confidence) and TOI-1235 b (95% confidence) respectively. Using a Parker wind model, we cap the mass-loss at $>$0.25 $\mathrm M_{\oplus}$ Gyr$^{-1}$ and $>$0.2 $\mathrm M_{\oplus}$ Gyr$^{-1}$ for GJ 9827 b and d, respectively (99% confidence), and $>$0.05 $\mathrm M_{\oplus}$ Gyr$^{-1}$ for TOI-1235 b (95\% confidence) for a representative wind temperature of 5000 K. Our observed results for the three planets are more consistent with the predictions from photoevaporation and/or core-powered mass-loss models than the gas-poor formation models. However, more planets in the radius-gap regime around the low-mass stars are needed to robustly predict the atmospheric evolution in planets around low-mass stars.Comment: Accepted for MNRAS. 12 pages, 15 figure

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease

Reproductive health and lifestyle factors associated with health-related quality of life among perinatally HIV-infected adolescents in Uganda

Background With increased survival of perinatally HIV - infected adolescents due to antiretroviral therapy (ART), the focus of HIV care has shifted to health-related quality of life (HRQoL) as a measure of disease progression, effects of ART co-morbidity and prognosis. We assessed factors associated with better HRQoL in perinatally HIV -infected adolescents in Uganda by determining the associations between sexual and reproductive health (SRH) or lifestyle experiences on HRQoL. Methods In a cross-sectional study, data on SRH, lifestyle experiences, socio demographic factors, communication with parents on sexuality and satisfaction of SRH services in ART clinics were collected from 614 HIV perinatally infected adolescents aged 10–19 using an interviewer-administered survey questionnaire. HRQoL data were collected using the Medical Outcomes Study HIV Health Survey instrument (MOS-HIV). Factors associated with better HRQoL were analysed using multiple logistic regression. Results The mean age was 16.2 ± 2.1 years, 362 (58.8 %) were females and 210 (34.2 %) were sexually active. Adolescents on ART were twice likely to present with better physical health (AOR = 2.07, 95 % CI: 1.24–3.46) and four times more likely to present with better mental health (AOR = 3.9, 95 % CI: 2.22–6.92) than those who were not on ART. There were no statistically significant associations between SRH (ever had sex, ever been pregnant, condom use, contraceptive use) or life style factors and physical health or mental health. Those with secondary or tertiary education were more likely to present with a better mental health (AOR = 5.3, 95 % CI: 1.86–15.41) compared those who had attained primary or no education. Participants who desired to have a child in future more likely (AOR 1.7, 95 % CI: 1.05–3.00) to present with a better mental health. Lack of communication with guardians on sexuality (AOR = 0.6, 95 % CI: 0.40–0.89), or dissatisfaction with SRH services (AOR 0.34, 95 % CI: 0.18–0.62) were associated with poorer mental health. Conclusion Among perinatally HIV-infected adolescents in Uganda, being on ART was associated with better physical and mental health while lack of communication with guardians on sexuality or dissatisfaction with SRH services was associated with poor mental health. Adolescents with pregnancy intentions were more likely to have a better mental health

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery