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The rapid global spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has created an unprecedented healthcare crisis. The treatment for the severe respiratory illness caused by this virus is primarily symptomatic at this point, although the usage of a broad antiviral drug Remdesivir has been allowed on emergency basis by the Food and Drug Administration (FDA). The ever-increasing death toll highlights an urgent need for development of specific antivirals. In this work, we have utilized docking and simulation methods to identify small molecule inhibitors of SARS-CoV-2 Membrane (M) and Envelope (E) proteins, which are essential for virus assembly and budding. A total of 70 compounds from an Indian medicinal plant source (Azadirachta indica or Neem) were virtually screened against these two proteins and further analyzed with molecular dynamics simulations, which resulted in the identification of a few common compounds with strong binding to both structural proteins. The compounds bind to biologically critical regions of M and E, indicating their potential to inhibit the functionality of these components. We hope that our computational approach may result in the identification of effective inhibitors of SARS-CoV-2 assembly. Communicated by Ramaswamy H. Sarma

Pseudomonas aeruginosa is one of the most common pathogens associated with nosocomial infections and a great concern to immunocompromised individuals especially in the cases of cystic fibrosis, AIDS and burn wounds. The pathogenicity of P. aeruginosa is largely directed by the quorum sensing (QS) system. Hence, QS may be considered an important therapeutic target to combat P. aeruginosa infections. The anti-quorum sensing and anti-biofilm efficacy of aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) against P. aeruginosa PAO1 were assessed. At the sub-inhibitory concentration, 5-HMF suppressed the production of QS-controlled virulence phenotypes and biofilm formation in P. aeruginosa. It was also able to significantly enhance the survival rate of C. elegans infected with P. aeruginosa. The in silico studies revealed that 5-HMF could serve as a competitive inhibitor for the auto-inducer molecules as it exhibited a strong affinity for the regulatory proteins of the QS-circuits i.e. LasR and RhlR. In addition, a significant down-regulation in the expression of QS-related genes was observed suggesting the ability of 5-HMF in mitigating the pathogenicity of P. aeruginosa.

Viroporins are oligomeric, pore forming, viral proteins that play critical roles in the life cycle of pathogenic viruses. Viroporins like HIV-1 Vpu, Alphavirus 6 K, Influenza M2, HCV p7, and Picornavirus 2B, form discrete aqueous passageways which mediate ion and small molecule transport in infected cells. The alterations in host membrane structures induced by viroporins is essential for key steps in the virus life cycle like entry, replication and egress. Any disruption in viroporin functionality severely compromises viral pathogenesis. The envelope (E) protein encoded by coronaviruses is a viroporin with ion channel activity and has been shown to be crucial for the assembly and pathophysiology of coronaviruses. We used a combination of virtual database screening, molecular docking, all-atom molecular dynamics simulation and MM-PBSA analysis to test four FDA approved drugs - Tretinoin, Mefenamic Acid, Ondansetron and Artemether - as potential inhibitors of ion channels formed by SARS-CoV-2 E protein. Interaction and binding energy analysis showed that electrostatic interactions and polar solvation energy were the major driving forces for binding of the drugs, with Tretinoin being the most promising inhibitor. Tretinoin bound within the lumen of the channel formed by E protein, which is lined by hydrophobic residues like Phe, Val and Ala, indicating its potential for blocking the channel and inhibiting the viroporin functionality of E. In control simulations, tretinoin demonstrated a lower binding energy with a known target as compared to SARS-CoV-2 E protein. This work thus highlights the possibility of exploring Tretinoin as a potential SARS-CoV-2 E protein ion channel blocker and virus assembly inhibitor, which could be an important therapeutic strategy in the treatment for coronaviruses., Highlights • Screened a database of 1806 small molecule compounds from DrugBank for potential SARS CoV-2 E protein inhibitors. • Tested four FDA-approved drugs Tetinoin, Mefenamic acid, Ondansetron and Artemether as SARS CoV-2 E protein inhibitors. • Used a combination of molecular docking, MD simulations and MM-PBSA analysis to propose Tretinoin as a promising inhibitor.

Anti-quorum sensing and anti-biofilm efficacy of Cinnamic acid against Pseudomonas aeruginosa was comparatively assessed with respect to potent quorum sensing inhibitor, Baicalein. At sub-lethal concentration, Cinnamic acid effectively inhibited both the production of the QS-dependent virulence factors and biofilm formation in P. aeruginosa without affecting the viability of the bacterium. The phytocompound interfered with the initial attachment of planktonic cells to the substratum thereby causing reduction in biofilm development. In addition, the in vivo study indicated that the test compound protected Caenorhabditis elegans from the virulence factors of P. aeruginosa leading to reduced mortality. The in silico analysis revealed that Cinnamic acid can act as a competitive inhibitor for the natural ligands towards the ligand binding domain of the transcriptional activators of the quorum sensing circuit in P. aeruginosa, LasR and RhlR. The findings suggest that Cinnamic acid may serve as a novel quorum sensing based anti-infective in controlling P. aeruginosa infections.

Viruses are parasite by nature and they are responsible for many diseases. Inhibitor development is very difficult for viruses due to their rapid mutative nature. A common approach for treating virus infection is targeting them at the genomic level and an encapsulation mechanism can be one of the targets. Sesbania mosaic virus (SeMV) is a spherical virus and its capsid is formed by a coat protein, which contains the Arginine Rich Motif (ARM). This ARM interacts with RNA operator loops present in their genome and starts encapsulation. Though the structure of SeMV was already solved by crystallography, it lacks the critical ARM domain. We predicted the full-length three-dimensional structure of this protein by using crystal structure (lacking ARM) as a template along with tertiary structure of RNA operator loops. Docking studies were performed to discover the interacting residues of protein and RNA which are driving protein and RNA to interact with each other. We observed that these interactions lead to conformation changes in the coat protein structure, which starts genome encapsulation process. The ARM region is found to be crucial for these interactions. Molecular dynamics simulation studies were performed to check the conformational changes and free energy landscapes were generated to check the viability of these changes in terms of energy. In this work we proposed one RNA operator loop that is responsible for noticeable conformational changes in the SeMV structure and might be involved in the activation of the viral protein. The results of this in silico study can be tested further through in vitro studies and can be used to stop encapsulation.

LGP2, a member of retinoic acid inducible gene-I like receptors (RLR), encoded by the gene DHX58 in human induces antiviral response against many RNA viruses. The LGP2 shares a considerable similarity to the amino acid sequence of Hef Helicase Domain, the helicase domain of RIG-I-like protein helicase-associated endonuclease (Hef), which is involved in RNA binding. Earlier studies suggest that RLR contains a conserved C-terminal domain (CTD), which is responsible for the binding specificity to the viral RNAs and C-terminal domain of LGP2 also takes part in RNA binding. The present study is aimed to explore the interactions of LGP2 and RNA, thereby finding the crucial residues for the interaction, with the help of in-silico tools. The predicted crucial residues were validated by docking and molecular dynamics simulation studies as well as by fitting the model on a LGP2 density map. Our results in this study suggest that the residues in the helicase domain of LGP2 are crucial for RNA binding and it is positioned around the groove region of LGP2. Though earlier experimental studies identified the RNA binding residues, but our in silico binding studies with the full length LGP2 predicted some additional residues that can be valuable

The capability of performing an array of functions with its single subunit structure makes T7 RNA polymerase (T7RNAP) as one of the simplest yet attractive target for various investigations ranging from structure determinations to several biological tests. In this study, with the help of molecular dynamics (MD) calculations and molecular docking, we investigated the effect of varying pH conditions on conformational flexibility of T7RNAP. We also studied its effect on the interactions with a well established inhibitor (heparin), substrate GTP and T7 promoter of T7RNAP. The simulation studies were validated with the help of three dimensional reconstructions of the polymerase at different pH environments using transmission electron microscopy and single particle analysis. On comparing the simulated structures, it was observed that the structure of T7RNAP changes considerably and interactions with its binding partners also changes as the pH shifts from basic to acidic. Further, it was observed that the C-terminal end plays a vital role in the inefficiency of the polymerase at low pH. Thus, this in-silico study may provide a significant insight into the structural investigations on T7RNAP as well as in designing potent inhibitors against it in varying pH environments.

Plants in nature may face a wide range of favorable or unfavorable biotic and abiotic factors during their life cycle. Any of these factors may cause stress in plants; therefore, they have to be more adaptable to stressful environments and must acquire greater response to different stresses. The objective of this study is to retrieve and arrange data from the literature in a standardized electronic format for the development of information resources on potential stress responsive genes in Arabidopsis thaliana. This provides a powerful mean for manipulation, comparison, search, and retrieval of records describing the nature of various stress responsive genes in Arabidopsis thaliana. The database is based exclusively on published stress tolerance genes associated with plants.

HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product, and is an attractive target for new anti-HIV drugs. Integrase is an enzyme produced by a retrovirus (such as HIV) that enables its genetic material to be integrated into the DNA of the infected cell. Raltegravir and Elvitegravir are two important drugs against integrase., Comment: 9 pages, 6 tables