The emerging new Coronaviridae member, nCoV 19, outbreak announced a pandemic by WHO with an increased morbidity and mortality rate worldwide. nCoV 19 known as the third highly pathogen coronavirus in the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), the nCoV 19. The renin-angiotensin (RAS) signaling pathway, oxidative stress and cell death, cytokines storm and endothelial dysfunction are four major pathways involved in the pathogenesis of nCoV 19. Acute respiratory distress syndrome (ARDS) generally develops with a massive oxidative/nitrosative stress following virus entry and RAS activation. The DNA damage subsequent to oxidative burst activates poly-ADP ribose polymerase-1 (PARP-1), viral macrodomain (NSP3) poly (ADP-ribose) glycohydrolase (PARG) and transient receptor potential channel, melastatin 2 (TRPM2) in a sequential manner ultimately leading to apoptosis and necrosis due to NAD and ATP depletion. Regarding the molecular mechanisms involved in nCoV 19 pathogenesis, angiotensin II receptor blockers and/or PARP, PARG and TRPM2 blockers could be engaged as therapeutic candidates for inhibition of RAS and quenching oxidative stress, respectively. In this review, the molecular aspects of nCoV 19 pathogenesis would be studied precisely and possible therapeutic targets would be proposed. It is recommended to evaluate the proposed drugs and supplements via registered clinical trials along with conventional guideline-based multi-drug regimen.

New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-β-lactamases in experimental studies.

With the progressive and ever-increasing antibacterial resistance pathway, the need for novel antibiotic design becomes critical. Sulfonamides are one of the more effective antibiotics against bacteria. In this work, several novel sulfonamide hybrids including coumarin and isoxazole group were synthesized in five steps starting from coumarin-3-carboxylic acid and 3-amino-5-methyl isoxazole and assayed for antibacterial activity. The samples were obtained in good to high yield and characterized by FT-IR, 13C-NMR, 1H-NMR, CHN and melting point techniques. 3D-QSAR is a fast, easy, cost-effective, and high throughput screening method to predict the effect of the compound's efficacy, which notably decreases the needed price for experimental drug assay. The 3D-QSAR model displayed acceptable predictive and descriptive capability to find r2 and q2 the pMIC of the designed compound. Key descriptors, which robustly depend on antibacterial activity, perhaps were explained by this method. According to this model, among the synthesized sulfonamide hybrids, 9b and 9f had the highest effect on the gram-negative and gram-positive bacteria based on the pMIC. The 3D-QSAR results were confirmed in the experimental assays, demonstrating that our model is useful for developing new antibacterial agents. The work proposes a computationally-driven strategy for designing and discovering new sulfonamide scaffold for bacterial inhibition.

This study showed that the rpoB region possesses high discriminatory power to identify the isolates to the species level. This marker showed high interspecies variability that might be useful for strain typing. The results also suggest the possibility of the existence of a predominant clone of A. baumannii among infected patients in Iran.

Sequence analysis of the 16S rRNA and rpoB spacer simultaneously was able to do identification of Acinetobacter spp. to species level. A.baumannii was identified as the most prevalent species with high antibiotic resistance. Other species showed lower frequencies ranged from 4 to 9 strains.

Resistance-nodulation-cell devision (RND) efflux pump variants have attracted a great deal of attention for efflux of many antibiotic classes, which leads to multidrug-resistant bacteria. The present study aimed to discover the interaction between the RND efflux pumps and antibiotics, find the conserved and hot spot residues, and use this information to target the most frequent RND efflux pumps. Protein sequence and 3D conformational alignments, pharmacophore modeling, molecular docking, and molecular dynamics simulation were used in the first level for discovering the function of the residues in interaction with antibiotics. In the second level, pharmacophore-based screening, structural-based screening, multistep docking, GRID MIF, pharmacokinetic modeling, fragment molecular orbital, and MD simulation were utilized alongside the former level information to find the most proper inhibitors. Five conserved residues, containing Ala209, Tyr404, Leu415, Asp416, and Ala417, as well as their counterparts in other OMPs were evaluated as the crucial conserved residues. MD simulation confirmed that a number of these residues had a key role in the performance of the efflux antibiotics; therefore, some of them were hot spot residues. Fourteen ligands were selected, four of which interacted with all the crucial conserved residues. NPC100251 was the fittest OMP inhibitor after pharmacokinetic computations. The second-level MD simulation and FMO supported the efficacy of the NPC100251. It was exhibited that perhaps OMPs worked as the intelligent and programable protein. NPC100251 was the strongest OMPs inhibitor, and may be a potential therapeutic candidate for MDR infections.

Background: The SARS-CoV-2 virus is a new highly contagious Coronavirus with a positive-sense RNA encoding 16 non-structural proteins (nsps16, nsp15, nsp3). In this study, the coronavirus pathogenicity and the losartan functional ligand for inhibiting TRPM2 and macrodomain have been molecularly evaluated.Material and method: In this study, the structures of macrodomain binding ADP ribose in CoVs and human Transient Receptor Potential Cation Channel Subfamily M Member 2 (TRPM2) protein were downloaded from protein data bank. Then, a virtual screening was done to recognize the hit compounds from GalaXi_2019-10, KnowledgeSpace_2019-05, and REALspace_2019-12 databases. This collection, then, was imported to the ligandScout software, on the base of Adenosine Diphosphate Ribose (ADPR) pharmacophore model. Result: Among seven compounds, five compounds were finally evaluated as the structural analogs of ADPR or other nucleotides, from which one compound was a non-FDA-approved sulphonamide and was removed. The other compound, losartan, was finally selected for molecular docking and molecular dynamic simulation. According to the virtual screening and docking, losartan was candidate as an effective ligand for TRPM2 and macrodomain. Conclusion: In the current study losartan earned a proper dock score and binding affinity to create the complexes with TRPM2 and macrodomain. The inhibitory effect of losartan on PARP has been shown and it could interfere positively in several points (PARP, PARG- macrodomain and TRPM2) and decreases oxidative stress and apoptosis in COVID-19.

New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for new Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with new Delhi metallo-β-lactamase. 3D conformational alignment and protein sequence alignment of all new Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Then the conserved and crucial residues in the catalytic activity of metallo-β-lactamases were detected. These residues had similar 3D coordinates in the 3D conformational alignment. So it is possible that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all new Delhi metallo-β-lactamase and metallo-β-lactamases in experimental studies.