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Claudin polymers constitute the tight junction (TJ) backbone that forms paracellular barriers, at least for bigger solutes. While some claudins also seal the barrier for small electrolytes, others form ion channels. For cation-selective claudin-15 and claudin-10b, structural models of channels embedded in homo-polymeric strands have been suggested. Here, we generated a model for the prototypic anion-selective claudin-10a channel. Based on previously established claudin-10b models, dodecamer homology models of claudin-10a embedded in two membranes were analyzed by molecular dynamics simulations. The results indicate that both claudin-10 isoforms share the same strand and channel architecture: Sidewise unsealed tetrameric pore scaffolds are interlocked with adjacent pores via the β1β2 loop of extracellular segment 1. This leads to TJ-like strands with claudin subunits arranged in four joined rows in two opposing membranes. Several but not all cis- and trans-interaction modes are indicated to be conserved among claudin-10a, -10b, and -15. However, pore-lining residues that differ between claudin-10a and -10b (i.e., R33/I35, A34/D36, K69/A71, N54/D56, H60/N62, R62/K64) result in opposite charge selectivity of channels. This was supported by electric field simulations for both claudins and is consistent with previous electrophysiological studies. In summary, for the first time, a structural and mechanistic model of complete and prototypic paracellular anion channels is provided. This improves understanding of epithelial paracellular transport. [ABSTRACT FROM AUTHOR]

JAK1 plays a significant role in the intracellular signaling by interacting with cytokine receptors in different types of cells and is linked to the pathogenesis of various cancers and in the pathology of the immune system. In this study, ligand-based pharmacophore modeling combined with virtual screening and molecular docking methods was incorporated to identify the potent and selective lead compounds for JAK1. Initially, the ligand-based pharmacophore models were generated using a set of 52 JAK1 inhibitors named C-2 methyl/hydroxyethyl imidazopyrrolopyridines derivatives. Twenty-seven pharmacophore models with five and six pharmacophore features were generated and validated using potency and selectivity validation methods. During potency validation, the Guner-Henry score was calculated to check the accuracy of the generated models, whereas in selectivity validation, the pharmacophore models that are capable of identifying selective JAK1 inhibitors were evaluated. Based on the validation results, the best pharmacophore models ADHRRR, DDHRRR, DDRRR, DPRRR, DHRRR, ADRRR, DDHRR, and ADPRR were selected and taken for virtual screening against the Maybridge, Asinex, Chemdiv, Enamine, Lifechemicals, and Zinc database to identify the new molecules with novel scaffold that can bind to JAK1. A total of 4,265 hits were identified from screening and checked for acceptable drug-like properties. A total of 2,856 hits were selected after ADME predictions and taken for Glide molecular docking to assess the accurate binding modes of the lead candidates. Ninety molecules were shortlisted based on binding energy and H-bond interactions with the important residues of JAK1. The docking results were authenticated by calculating binding free energy for protein–ligand complexes using the MM-GBSA calculation and induced fit docking methods. Subsequently, the cross-docking approach was carried out to recognize the selective JAK1 lead compounds. Finally, top five lead compounds that were potent and selective against JAK1 were selected and validated using molecular dynamics simulation. Besides, the density functional theory study was also carried out for the selected leads. Through various computational studies, we observed good potency and selectivity of these lead compounds when compared with the drug ruxolitinib. Compounds such as T5923555 and T5923531 were found to be the best and can be further validated using in vitro and in vivo methods. [ABSTRACT FROM AUTHOR]

In the past two decades, the structural biology studies on G‐protein coupled receptors (GPCRs) are on the rise. Understanding the relation between the structure and function of GPCRs is important as they play a huge role in various signaling mechanisms in a eukaryotic cell. Somatostatin receptor 3 (SSTR3), one of the GPCRs, is one such important receptor which oversees different cellular processes including cell‐to‐cell signaling. However, the information available regarding the structural features of SSTR3 responsible for their bioactivity is scarce. In this study, we report a structural understanding of SSTR3‐ligand binding that could be helpful in demystifying the structural complexities related to functioning of the receptor. An integrated protocol consisting of different computational structural biology tools including protein structure prediction via comparative modeling, binding site characterization, three‐dimensional quantitative structure–activity relationship based on comparative molecular field analysis and comparative molecular similarity indices analysis, density functional theory, and molecular dynamics simulations were performed. Different understandings from the simulation of SSTR3‐ligand complexes, mainly the conditions that are favorable for the formation of lowest bioactive state of SSTR3 ligands are reported. In addition to that, we report the important physicochemical descriptors of SSTR3 ligands that could significantly influence their bioactivity. The results of the study could be helpful in developing novel SSTR3 ligands (both agonists and antagonists) with high potency and receptor selectivity. [ABSTRACT FROM AUTHOR]

Freshwater fish Pangasius sutchi was used in this study as a vertebrate model. We evaluated the induction of certain antioxidant enzymes in various vital organs. The radioprotective efficacy of Gymnema sylvestre leaves extract (GS) [25 mg/kg Body Weight (B.W)] and its bioactive compound Gymnemagenin (GG) [0.3 mg/kg B.W] was compared with Amifostine (Ami), the only radioprotector clinically approved by the US-FDA [Ami- 83.3 mg/kg B.W] against different doses of gamma radiation – 60Co (Lethal Dose: LD30-9.2 Gy, LD50-10.2 Gy and LD70-11.4 Gy). This study was done via stress marker enzymes, cell cycle analysis (CCA) and DNA damage assay prediction with molecular docking, which are reported here for the first time. The results indicate an elevated LPO level and decreased level of CAT, SOD and GSH due to oxidative stress initiation by 60Co Ionizing Radiation (IR) on 4th day and slightly reduced on 32nd day while the reverse observed when the fishes were pretreated with Ami, GS and GG. Similarly, CCA and dead/live cells counts were conducted with pretreatment of Ami, GS and GG against 60Co IR dose (LD50-10.2 Gy). In CCA, G0/G1 phase was observed to be the highest in Ami and lowest in GG, against 60Co IR doses 10.2 Gy which was 51.76 ± 7.55. The dead cells range observed in pretreated group of Ami, GS and GG was lowest in Ami and highest in GG and live cells (highest in Ami and lowest in GG) as compared to 60Co IR group (86.43 ± 3.42 and 8.77 ± 5.95). Thus, antioxidant profile improvement by oxidative stress reduction and gradual progression of different phases of cell cycle except the apoptotic phase along with the live cells counts indicates that the radio-protective efficacy of GS is similar to Ami. Predictive assessment was carried out by docking of Ami, various components of GS with p53, NF-κβ cells and Rad51 proteins structures responsible for CCA, apoptosis and repair mechanism. These structural proteins were docked with other structural proteins like USP7, TNF-α and partner and localizer of BRCA2 associated (PALB2/BRCA2) complex which made us perform these systemic efforts to find the functional activity of these known radio-protectants. [ABSTRACT FROM AUTHOR]

In Quantitative Structure‐Activity Relationship (QSAR) studies, selection of an appropriate method to assign the partial charge is crucial to derive a reliable model. The prediction accuracy of 3D‐QSAR models depends mainly on the method by which the partial charges were calculated. Therefore, we are interested in examining the effects of empirical and semi‐empirical partial charges on 3D‐QSAR methods, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The feasibility and performance of these charges have been tested on Janus Kinase 2 inhibitors. Both empirical (Gasteiger‐Huckel, Del‐Re, Gasteiger Marsili, Huckel, Merck Molecular Force Field 94 (MMFF94), Pullman) and semi‐empirical (Austin Model 1 (AM1), Parameterized Model 3 (PM3), Recife Model 1 (RM1), and Modified Neglect of Diatomic Overlap (MNDO)) charges exhibited statistically significant quality. Among them, MMFF94, MNDO and AM1 charges yielded higher cross‐validation correlation coefficient (q2) values whereas Del‐Re and MMFF94 charges produced topmost predictive ability (r2pred). Overall, MMFF94 in CoMFA and MMFF94 and MNDO in CoMSIA models was found to be the best charges when both q2 and r2pred values were used as an evaluation criterion. Our results could provide an idea of selection of appropriate charge rather than using default charge to enhance the quality of 3D‐QSAR when prediction accuracy and predictive ability were employed. [ABSTRACT FROM AUTHOR]

• Wild bergamot (Monarda fistulosa) essential oil vapours could effectively suppress the in vitro growth of Colletotrichum musae and Lasiodiplodia theobromae at 4 μL per Petriplate. • Molecular docking studies suggested that thymol, carvacrol and cinnamyl carbanilate were the components responsible for the antifungal activity. • The values of the molecular descriptors obtained through conceptual DFT study also suggested that thymol, carvacrol and cinnamyl carbanilate were highly active components. • Postharvest treatment of banana fruits using wild bergamot essential oil could extend the life of the fruits through sustainable means. This study aimed to examine the antifungal activity of wild bergamot (Monarda fistulosa) essential oil on Colletotrichum musae and Lasiodiplodia theobromae , the causative organisms of anthracnose and crown-rot diseases of banana fruits, respectively. Chitin synthase is a promising target for antifungal compounds, since it is involved in synthesizing chitin, which forms a major proportion of the fungal cell wall. Disc volatilisation method was employed to assess the in vitro antifungal activity of the oil. The vapours of this essential oil at 4 μL per Petriplate exhibited 100% growth inhibition of both the fungal pathogens, and at 66.66 μLL−1 , it significantly (P <0.05) reduced the incidence and severity of anthracnose and crown-rot diseases in artificially wounded and infected fruits. The chemical composition of wild bergamot essential oil was determined by GC-MS technique and the components of the essential oil were docked against chitin synthase to determine the components responsible for antifungal activity. Chitin synthase was modelled by de novo approach due to non-availability of the 3D structure. The in silico techniques such as molecular docking and conceptual DFT revealed that the major components of the essential oil namely thymol, carvacrol and cinnamyl carbanilate manifested the best antifungal activity. This illustrates effective inhibition of the major postharvest diseases of banana by wild bergamot essential oil. [ABSTRACT FROM AUTHOR]

As the aim of this present study, a proteinaceous α-amylase inhibitor has been isolated from the rhizome of Cheilocostus specious ( C . speciosus ) and was purified using DEAE cellulose anion exchange chromatography followed by gel filtration using Sephacryl-S-200 column. The purity and molecular mass of the purified inhibitor was determined by SDS-PAGE and LC-MS respectively. The molecular mass of the purified inhibitor was determined to be 31.18 kDa. Protein-protein docking was also carried out as molecular model. Model validation methods such as Ramachandran plot and Z -score plot were adopted to validate the structural description (sequence analysis) of proteins. The inhibitory activity was confirmed using spectrophotometric and reverse zymogram analyses. This 31.18 kDa protein from C . speciosus inhibited the activity of fungal α-amylase by 71% at the level of ion exchange chromatography and 96% after gel filtration. The inhibition activity of the α-amylase inhibitor was stable and high at optimum pH 6 (52.2%) and temperatures of 30–40 °C (72.2%). Thus it was suggested that the main responsible for the versatile biological and pharmacological activities of C . speciosus is due to its primary metabolites (proteins) only. [ABSTRACT FROM AUTHOR]

Purpose: Freshwater fish Pangasius sutchi was used in this study as a vertebrate model. We evaluated the induction of certain antioxidant enzymes in various vital organs. The radioprotective efficacy of Gymnema sylvestre leaves extract (GS) [25   mg/kg Body Weight (B.W)] and its bioactive compound Gymnemagenin (GG) [0.3   mg/kg B.W] was compared with Amifostine (Ami), the only radioprotector clinically approved by the US-FDA [Ami- 83.3   mg/kg B.W] against different doses of gamma radiation - 60 Co (Lethal Dose: LD 30 -9.2   Gy, LD 50 -10.2   Gy and LD 70 -11.4   Gy)., Materials and Methods: This study was done via stress marker enzymes, cell cycle analysis (CCA) and DNA damage assay prediction with molecular docking, which are reported here for the first time. The results indicate an elevated LPO level and decreased level of CAT, SOD and GSH due to oxidative stress initiation by 60 Co Ionizing Radiation (IR) on 4th day and slightly reduced on 32nd day while the reverse observed when the fishes were pretreated with Ami, GS and GG. Similarly, CCA and dead/live cells counts were conducted with pretreatment of Ami, GS and GG against 60 Co IR dose (LD 50 -10.2   Gy)., Results: In CCA, G0/G1 phase was observed to be the highest in Ami and lowest in GG, against 60 Co IR doses 10.2   Gy which was 51.76   ±   7.55. The dead cells range observed in pretreated group of Ami, GS and GG was lowest in Ami and highest in GG and live cells (highest in Ami and lowest in GG) as compared to 60 Co IR group (86.43   ±   3.42 and 8.77   ±   5.95). Thus, antioxidant profile improvement by oxidative stress reduction and gradual progression of different phases of cell cycle except the apoptotic phase along with the live cells counts indicates that the radio-protective efficacy of GS is similar to Ami., Conclusion: Predictive assessment was carried out by docking of Ami, various components of GS with p53, NF-κβ cells and Rad51 proteins structures responsible for CCA, apoptosis and repair mechanism. These structural proteins were docked with other structural proteins like USP7, TNF-α and partner and localizer of BRCA2 associated (PALB2/BRCA2) complex which made us perform these systemic efforts to find the functional activity of these known radio-protectants.

Somatostatin receptor 1 (SSTR1), a subtype of somatostatin receptors, is involved in various signaling mechanisms in different parts of the human body. Like most of the G-protein-coupled receptors (GPCRs), the available information on the structural features of SSTR1 responsible for the biological activity is scarce. In this study, we report a molecular-level understanding of SSTR1-ligand binding, which could be helpful in solving the structural complexities involved in SSTR1 functioning. Based on a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), we have identified that an electronegative, less-bulkier, and hydrophobic atom substitution can substantially increase the biological activity of SSTR1 ligands. A density functional theory (DFT) study has been followed to study the electron-related properties of the SSTR1 ligands and to validate the results obtained via the 3D-QSAR study. 3D models of SSTR1-ligand systems have been embedded in lipid-lipid bilayer membranes to perform molecular dynamics (MD) simulations. Analysis of the MD trajectories reveals important information about the crucial residues involved in SSTR1-ligand binding and various conformational changes in the protein that occur after ligand binding. Additionally, we have identified the probable ligand-binding site of SSTR1 and validated it using MD. We have also studied the favorable conditions that are essential for forming the most stable and lowest-energy bioactive conformation of the ligands inside the binding site. The results of the study could be useful in constructing more potent and novel SSTR1 antagonists and agonists., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

In the present work, molecular modeling studies have been reported on a series of diazine indole acetic acid derivatives to analyze the structure-activity relationship studies of CRTH2 using fragment (Topomer CoMFA and HQSAR) and field (CoMFA and CoMSIA) based QSAR methods. Twenty-six compounds were used as a training set to establish the model, and six compounds were used as a test set to validate the model. The generated models exhibited good statistical results such as correlation coefficient (r2) and the cross-validated correlation coefficient (q2). Topomer CoMFA analysis yielded the q2 of 0.610 and r2 of 0.981. HQSAR model generated using bond and connectivity as fragment distinction and 3-6 as fragment size has the q2 value of 0.707 and conventional r2 value of 0.892 with five components. CoMFA model was assessed by cross-validated q2 value of 0.543 and r2 value of 0.901 with steric and electrostatic fields. CoMSIA model generated using steric, hydrophobic and donor fields with q2 value of 0.550 and r2 value of 0.888 was found to be the optimal model among the various models generated. The contour maps were generated to analyze the important structural features that regulate their inhibitory potency. From the result of contour maps we have suggested the critical sites for chemical modification which will be useful in designing potent compounds with improved activity.