Sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA (ssRNA) virus, responsible for severe acute respiratory disease (COVID-19). A large number of natural compounds are under trial for screening compounds, possessing potential inhibitory effect against the viral infection. Keeping in view the importance of marine compounds in antiviral activity, we investigated the potency of some marine natural products to target SARS-CoV-2 main protease (M pro) (PDB ID 6MO3). The crystallographic structure of M pro in an apo form was retrieved from Protein Data Bank and marine compounds from PubChem. These structures were prepared for docking and the complex with good docking score was subjected to molecular dynamic (MD) simulations for a period of 100 ns. To measure the stability, flexibility, and average distance between the target and compounds, root mean square deviations (RMSD), root mean square fluctuation (RMSF), and the distance matrix were calculated. Among five marine compounds, C-1 (PubChem CID 11170714) exhibited good activity, interacting with the active site and surrounding residues, forming many hydrogen and hydrophobic interactions. The C-1 also attained a stable dynamic behavior, and the average distance between compound and target remains constant. In conclusion, marine natural compounds may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19.

Combined drug repurposing and virtual screening strategies with molecular dynamics simulation identified potent inhibitors for SARS-CoV-2 main protease (3CLpro), Journal of Biomolecular Structure and Dynamics,

Graphical abstract

Patch-clamp recordings indicated the presence of P2X7 receptors at neural progenitor cells (NPCs) in the subgranular zone of the dentate gyrus in hippocampal brain slices prepared from transgenic nestin reporter mice. The activation of these receptors caused inward current near the resting membrane potential of the NPCs, while P2Y1 receptor activation initiated outward current near the reversal potential of the P2X7 receptor current. Both receptors were identified by biophysical/pharmacological methods. When the brain slices were prepared from mice which underwent a pilocarpine-induced status epilepticus or when brain slices were incubated in pilocarpine-containing external medium, the sensitivity of P2X7 and P2Y1 receptors was invariably increased. Confocal microscopy confirmed the localization of P2X7 and P2Y1 receptor-immunopositivity at nestin-positive NPCs. A one-time status epilepticus in rats caused after a latency of about 5 days recurrent epileptic fits. The blockade of central P2X7 receptors increased the number of seizures and their severity. It is hypothesized that P2Y1 receptors after a status epilepticus may increase the ATP-induced proliferation/ectopic migration of NPCs; the P2X7 receptor-mediated necrosis/apoptosis might counteract these effects, which would otherwise lead to a chronic manifestation of recurrent epileptic fits.

Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic have been recognized as the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain. Conclusion: The current study was designed to focus on the allosteric regulation (autoinhibition) of the of Shp2 protein. Subsequently, it will cover the last 10-year recap of Shp2 protein, their role in cancer, and regulation in numerous ways (allosteric regulation).

ObjectivesTo explore the association of maternal education and empowerment with childhood polio vaccination using nationally representative data of Pakistani mothers in a reproductive age group.DesignCross-sectional.SettingSecondary analysis of Pakistan Demographic and Health Survey (PDHS), 2012–2013 data was performed.ParticipantsOf the 13 558 mothers included in the survey sample, 6982 mothers were able to provide information regarding polio vaccinations.Main outcome measuresPolio vaccination coverage among children aged up to 5 years was categorised as complete vaccination (all four oral polio vaccine (OPV) doses), incomplete vaccination, and no vaccination (zero OPV dose received). Mothers' empowerment status was assessed using standard ‘Measure DHS’ questions regarding their involvement in decision-making related to health, household possessions and visits among family and friends. Education was categorised as no education, primary, secondary and higher education. Results of multinomial regression analyses were reported as adjusted OR with 95% CI. We adjusted for age, wealth index, urban/rural residence, place of delivery, and antenatal and postnatal visits.ResultsOnly 56.4% (n=3936) of the children received complete polio vaccination. Women with no education had significantly higher odds of their child receiving no polio vaccination (OR 2.34, 95% CI 1.05 to 5.18; p<0.01) and incomplete vaccination (OR 1.40, 95% CI 1.04 to 1.87; p<0.01). Further, unempowered women also had significantly higher odds of not taking their child for any polio vaccination (OR 1.58, 95% CI 1.17 to 2.12; p<0.01) and incomplete vaccination (OR 1.18, 95% CI 1.00 to 1.41; p=0.04).ConclusionsIlliteracy, socioeconomic status and empowerment of women remained significant factors linked to poorer uptake of routine polio vaccination.

Resistance to key first-line drugs is a major hurdle to achieve the global end tuberculosis (TB) targets. A prodrug, pyrazinamide (PZA) is the only drug, effective in latent TB, recommended in drug resistance and susceptible Mycobacterium tuberculosis (MTB) isolates. The prodrug conversion into active form, pyrazinoic acid (POA), required the activity of pncA gene encoded pyrazinamidase (PZase). Although pncA mutations have been commonly associated with PZA resistance but a small number of resistance cases have been associated with mutationss in RpsA protein. Here in this study a total of 69 PZA resistance isolates have been sequenced for pncA mutations. However, samples that were found PZA resistant but pncA wild type ( pncA WT ), have been sequenced for rpsA and panD genes mutation. We repeated a drug susceptibility testing according to the WHO guidelines on 18 pncA WT MTB isolates. The rpsA and panD genes were sequenced. Out of total 69 PZA resistant isolates, 51 harbored 36 mutations in pncA gene (GeneBank Accession No. MH46111) while, fifteen different mutations including seven novel, were detected in the fourth S1 domain of RpsA known as C-terminal (MtRpsA CTD ) end. We did not detect any mutations in panD gene. Among the rpsA mutations, we investigated the molecular mechanism of resistance behind mutations, D342N, D343N, A344P, and I351F, present in the MtRpsA CTD through molecular dynamic simulations (MD). WT showed a good drug binding affinity as compared to mutants (MTs), D342N, D343N, A344P, and I351F. Binding pocket volume, stability, and fluctuations have been altered whereas the total energy, protein folding, and geometric shape analysis further explored a significant variation between WT and MTs. In conclusion, mutations in MtRpsA CTD might be involved to alter the RpsA activity, resulting in drug resistance. Such molecular mechanism behind resistance may provide a better insight into the resistance mechanism to achieve the global TB control targets.

<b><i>Background:</i></b> The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic has resulted in thousands of infections and deaths worldwide. Several therapies are currently undergoing clinical trials for the treatment of SARS-CoV-2 infection. However, the development of new drugs and the repositioning of existing drugs can only be achieved after the identification of potential therapeutic targets within structures, as this strategy provides the most precise solution for developing treatments for sudden epidemic infectious diseases. <b><i>Summary:</i></b> In the current investigation, crystal and cryo-electron microscopy structures encoded by the SARS-CoV-2 genome were systematically examined for the identification of potential drug targets. These structures include nonstructural proteins (Nsp-9; Nsp-12; and Nsp-15), nucleocapsid (N) proteins, and the main protease (M^pro). <b><i>Key Message:</i></b> The structural information reveals the presence of many potential alternative therapeutic targets, primarily involved in interaction between N protein and Nsp3, forming replication-transcription complexes (RTCs) which might be a potential drug target for effective control of current SARS-CoV-2 pandemic. RTCs consist of 16 nonstructural proteins (Nsp1-16) that play the most essential role in the synthesis of viral RNA. Targeting the physical linkage between the envelope and single-stranded positive RNA, a process facilitated by matrix proteins may provide a good alternative strategy. Our current study provides useful information for the development of new lead compounds against SARS-CoV-2 infections.