Gene network interaction analysis to elucidate the antimicrobial resistance mechanisms in the Clostridiumdifficile.

Antimicrobial resistance has caused chaos worldwide due to the depiction of multidrug-resistant (MDR) infective microorganisms. A thorough examination of antimicrobial resistance (AMR) genes and associated resistant mechanisms is vital to solving this problem. Clostridium difficile (C. difficile) is an opportunistic nosocomial bacterial strain that has acquired exogenous AMR genes that confer resistance to antimicrobials such as erythromycin, azithromycin, clarithromycin, rifampicin, moxifloxacin, fluoroquinolones, vancomycin, and others. A network of interactions, including 20 AMR genes, was created and analyzed. In functional enrichment analysis, Cellular components (CC), Molecular Functions (MF), and Biological Processes (BP) were discovered to have substantial involvement. Mutations in the rpl genes, which encode ribosomal proteins, confer resistance in Gram-positive bacteria. Full erythromycin and azithromycin cross-resistance can be conferred if more than one of the abovementioned genes is present. In the enriched BP, rps genes related to transcriptional regulation and biosynthesis were found. The genes belong to the rpoB gene family, which has previously been related to rifampicin resistance. The genes rpoB, gyrA, gyrB, rpoS, rpl genes, rps genes, and Van genes are thought to be the hub genes implicated in resistance in C. difficile. As a result, new medications could be developed using these genes. Overall, our observations provide a thorough understanding of C. difficile AMR mechanisms.

Exploration of NMI-MsCl mediated amide bond formation for the synthesis of novel 3,5-substituted-1,2,4-oxadiazole derivatives: synthesis, evaluation of anti-inflammatory activity and molecular docking studies.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives 9a-e and 10a-e in good to excellent yields by employing NMI-MsCl mediated amide bond formation reaction. The anti-inflammatory potential of the newly synthesized compounds were evaluated by anti-denaturation assay using diclofenac sodium as the reference drug. The compounds 9a and 9d demonstrated promising activity profile when compared to the reference standard. The SAR and molecular docking studies were also carried out for obtaining more details about the profound activity profile of the synthesized molecules. The synthesized compounds were docked against two target proteins TGF-ß and IL-1 by AutoDock vina and Auto Dock 4.2.

Design, synthesis and molecular docking studies of some 1-(5-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)piperazine derivatives as potential anti-inflammatory agents.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives in good to excellent yields. The anti-inflammatory potential of the newly synthesized compounds was evaluated by anti-denaturation assay using diclofenac sodium as the reference standard. Some of the compounds exhibited profound activity profile when compared to the standard drug. The molecular docking and SAR studies were carried out at the later stage for gaining more insights about the promising activity profile of the synthesized molecules.

Atranorin, an antimicrobial metabolite from lichen Parmotrema rampoddense exhibited in vitro anti-breast cancer activity through interaction with Akt activity.

Atranorin (ATR), lichenized secondary metabolite and depside molecule with several biological potentials such as antimicrobial, anticancer, anti-inflammatory, antinociceptive, wound healing and photoprotective activities. Cytotoxic reports of ATR are documented in several cancer cells and in vivo models but its molecular interaction studies are poorly understood. Therefore, in this present investigation, we have used the in silico studies with biological validation of the molecular targets for the anti-breast cancer mechanism of ATR. The molecular docking studies with the breast cancer oncoproteins such as Bcl-2, Bax, Akt, Bcl-w and Bcl-xL revealed the highest interaction was observed with the Akt followed by Bax, Bcl-xL and Bcl-2 & least with the Bcl-w proteins. The cytotoxicity studies showed ATR selectively inhibited MDA MB-231 and MCF-7 breast cancer cells in differential and dose-dependent manner with the IC50 concentration of 5.36 ± 0.85 µM and 7.55 ± 1.2 µM respectively. Further mechanistic investigations revealed that ATR significantly inhibited ROS production and significantly down-regulated the anti apoptotic Akt than Bcl-2, Bcl-xL and Bcl-w proteins with a significant increase in the Bax level and caspases-3 activity in the breast cancer cells when comparison with Akt inhibitor, ipatasertib. In vitro biological activities well correlated with the molecular interaction data suggesting that atranorin had higher interaction with Akt than Bax and Bcl-2 but weak interaction with Bcl-w and Bcl-xL. In this present study, the first time we report the interactions of atranorin with molecular targets for anti-breast cancer potential. Hence, ATR represents the nature-inspired molecule for pharmacophore moiety for design in targeted therapy.Communicated by Ramaswamy H. Sarma.

Molecular screening of antimalarial, antiviral, anti-inflammatory and HIV protease inhibitors against spike glycoprotein of coronavirus.

Coronavirus outbreak in December 2019 (COVID-19) is an emerging viral disease that poses major menace to Humans and it's a crucial need to find the possible treatment strategies. Spike protein (S2), a envelop glycoprotein aids viral entry into the host cells that corresponds to immunogenic ACE2 receptor binding and represents a potential antiviral drug target. Several drugs such as antimalarial, antibiotic, anti-inflammatory and HIV-protease inhibitors are currently undergoing treatment as clinical studies to test the efficacy and safety of COVID-19. Some promising results have been observed with the patients and also with high mortality rate. Hence, there is a need to screen the best CoV inhibitors using insilico analysis. The Molecular methodologies applied in the present study are, Molecular docking, virtual screening, drug-like and ADMET prediction helps to target CoV inhibitors. The results were screened based on docking score, H-bonds, and amino acid interactions. The results shows HIV-protease inhibitors such as cobicistat (-8.3kcal/mol), Darunavir (-7.4kcal/mol), Lopinavir (-9.1kcal/mol) and Ritonavir (-8.0 kcal/mol), anti-inflammatory drugs such as Baricitinib (-5.8kcal/mol), Ruxolitinib (-6.5kcal/mol), Thalidomide (-6.5kcal/mol), antibiotic drugs such as Erythromycin(-9.0kcal/mol) and Spiramycin (-8.5kcal/mol) molecules have good affinity towards spike protein compared to antimalarial drugs Chloroquine (-6.2kcal/mol), Hydroxychloroquine (-5.2kcal/mol) and Artemisinin (-6.8kcal/mol) have poor affinity to spike protein. The insilico pharmacological evaluation shows that these molecules exhibit good affinity of drug-like and ADMET properties. Hence, we propose that HIVprotease, anti-inflammatory and antibiotic inhibitors are the potential lead drug molecules for spike protein and preclinical studies needed to confirm the promising therapeutic ability against COVID-19.

Molecular Modelling and Insilico Engineering of PapMV-CP Towards Display and Development of Capripox Viral Like Particles Based on Immunogenic P32 Envelop Protein is the Homologous of the Vaccinia-Viral H3L Gene: An Insilico Approach.

Viral-like particles are assembled from capsid protein structural subunits of different viruses and have ability to establish research in biomedicals, like construction of novel safety vaccines, gene therapy vectors by delivering systems for nucleic acids, small biomolecules and diagnostics. Papaya Mosaic Viral nanoparticals can provide as a vaccine candidate helps to increase the immunity by fusing the epitope based peptide antigen. Capripox viruses are the genus comprises Lymphy skin-disease, Sheep and Goat pox Viruses are notified by The World Animal Health Organization (OIE) based on their economic impotence act as a transboundary animal diseases viruses of sheep, goat, and cattle's respectively. Plant viral based innovative vaccines have been emerged ineffective vaccine development. This research describes the engineering and development of a new vaccine candidate by display immunogenic peptide using the carrier capsid protein of Papaya Mosaic Virus. The Capripox virus P32 immunogenic protein is homologous of the vaccinia virus H3L gene displayed PapMV CP. The antigenicity of P32 protein epitope lowest score among epitopes C-terminally docked epitopes are EP6 > EP3 > EP8 as well the lowest score among epitopes N-terminally docked epitopes are EP8 > EP3 > EP6 presented on the N-terminus of PMV CP region which are found to be suitable for epitope display. And these modelled immunogenic peptide could be used to develop a viral like particles. Epitope based Antibody developed against immunogenic epitopic regions can contribute to a novel and robust protection from infection. As well might be used for developing cost effective detection kits for Transboundary animal disease viruses.