Structural basis for CCR6 modulation by allosteric antagonists.

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.

Explanation of major determinants of poverty using multivariate statistical approach and spatial technology: a case study on Birbhum district, West Bengal, India.

Poverty is not only the focal issue that has drawn worldwide attention but is also an essential issue in people's livelihoods. This research examines the primary factors of poverty in the Birbhum district. Multivariate statistical techniques have been used to identify the primary determinants. Ten parameters have been identified as significant drivers of poverty, six of which are physical, viz. slope, elevation, drainage density, pond frequency, soil texture, and rainfall. The remaining four sociocultural and economic parameters are literacy, major market center, population growth, and road density. A linear relationship has been established between the explanatory and response variables where the R-square or coefficient of determination value is 0.741, and this relationship explains more than 74% of the variables. The P-value of multi-linear regression is 0.000, which validates the model and permits the data for factor analysis to extract the major determinants. Factor analysis indicates that five essential factors have been found based on their eigenvalue viz., agro-climatic factor, infrastructural and educational factors, hydrological factor, demographic factor, and pedological factors. All the p-values of the correlation matrix are < 0.05, meaning all the relationships are valid and significant. This research also demonstrates the spatial analysis of data using GIS technology. The western part of the study area has been affected by the high influence of all factors due to the presence of plateau fringe and associated low productivity. The outcomes of the research are scientifically significant and this study helps the planners, higher authorities, and social workers to eradicate poverty from this region through formulating better policies and management.

Asymmetric nexus between air quality index and nationwide lockdown for COVID-19 pandemic in a part of Kolkata metropolitan, India.

The diffusion of COVID-19 or Coronavirus since last few months is the prime matter of concern for the entire world. The government of India had declared the complete lockdown from 24th March. After the second step lockdown, now third step lockdown was declared. So, India in Lockdown 3.0 situation. Although the economy of our country has severely been affected by the impact of lockdown, this situation is good for natural healing. Major metropolitan cities of India are trying to recover from various pollution. This study, therefore, attempts to analyze the trend of air pollution before and during a lockdown situation in Kolkata metropolitan and surrounding areas. To identify air pollution trends before and during the lockdown, the non-parametric Maan-Kendall test and Sen's slope estimator have been applied in this study. This research has been done based on air quality index data of the Kolkata metropolitan region's observatory stations. The time range of the data set is from mid of February to 2nd May. The study results show that air pollution has been reduced up to 80% in almost all the stations due to strict lockdown.

Oxidative Cyclization Approach to Benzimidazole Libraries.

An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4-C7 variation has traditionally relied on 1,2-dianiline building blocks, providing limited chemical space coverage. We have developed an amidine formation/oxidative cyclization sequence that enables anilines as a diversity set for benzimidazole C4-C7 SAR generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated oxidation to access both N-H and N-alkyl benzimidazoles. This library protocol has now been utilized for analog production in four medicinal chemistry projects. Additionally, the synthesis of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.

Chemical synthesis of the repeating unit of type Ia group B Streptococcus capsular polysaccharide.

The structure of the capsular polysaccharide (CPS) of serotype Ia group B Streptococcus (GBS) has been characterized for years, but its repeating unit, which is a challenging pentasaccharide with a branch and a difficult α-sialic acid linkage, has not been synthesized yet. In this report, an effective synthesis was developed for the serotype Ia GBS CPS repeating unit, which had a reactive functionality linked to its main-chain reducing end to enable further elaboration, such as coupling with carrier proteins. The target molecule was accomplished by a convergent [2 + 3] glycosylation strategy employing a sialo-disaccharide as donor and a branched trisaccharide as acceptor. The strategy was designed to suit the synthesis of oligomers of the repeating unit.

Stereocontrolled synthesis of the tricyclic ABC ring system of daphnicyclidin A.

An enantiocontrolled synthesis pathway has been developed to provide formation of tricyclic amine 7, representing the ABC ring system of the complex alkaloid daphnicyclidin A (1). Our efforts describe preparation of the Z-hexahydro-(1H)-azocine 29 and cyclization to construct the novel 4-azabicyclo[5.3.2]dodecane 31. Transannular reductive amination following the deprotection of 31 gave the desired tertiary amine 7.