Computational study of novel inhibitory molecule, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea, with high potential to competitively block ATP binding to the RNA dependent RNA polymerase of SARS-CoV-2 virus.

For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silico screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski's rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz. docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1 displayed higher docking score (-8.069 kcal/mol) and MM-GBSA binding free energy (-49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1 as better inhibitor. Overall, our systematic in silico study predicts the potential of compound 1 to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma.

Dysregulated Exosomes Result in Suppression of the Immune Response of Pregnant COVID-19 Convalescent Women.

A successful pregnancy outcome is dependent on a delicate balance between inflammatory and anti-inflammatory processes throughout the different trimesters. Interruption in this balance can lead to an adverse outcome resulting in pregnancy loss. Since late 2019, the emergence of the new SARS-CoV-2 virus has affected lives worldwide, including pregnant women; therefore, there is an urgent need to address different approaches in relation to prevention, diagnostics, and therapeutics. Early pregnancy is affected by SARS-CoV-2 infection leading to fetal demise. Available evidence also suggests that 90% of pregnant women infected with the SARS-CoV-2 virus seem to be asymptomatic. Nonetheless, it is still unclear how COVID-19 affects exosome production in pregnant women recovered from COVID-19 and how these exosomes regulate the adaptive immune response. In this study, we found several exosomes including CD9, CD31, CD40, CD45, CD41b, CD42a, CD62P, CD69, CD81, CD105, and HLA-DRDPDQ in the plasma of COVID-19-recovered pregnant women were significantly less abundant than the control group. Furthermore, to understand how these exosomes affect the adaptive immune response, we co-cultured the peripheral blood mononuclear cells (PBMCs) from healthy control (HC) pregnant women with exosomes of either Preg-HC or Preg-recovered COVID-19 women. We identified that Preg-recovered COVID-19 women have reduced capacity for the inflammatory cytokine TNF-α from cytotoxic CD8+ T cells. In summary, our study highlights that pregnant recovered COVID-19 women have reduced production of several exosomes and possess fewer immunogenic properties. Our study implicates that exosomes can control inflammation and antigen presentation capacity of immune cells, thus limiting the infection in pregnant women.

Fault Lines in India's COVID-19 Management: Lessons Learned and Future Recommendations.

With about 0.4-0.5 million COVID cases diagnosed every single day in a row over the past three weeks back in May 2021, India was at the epicenter of the global viral rampage. The catastrophe of this crisis was unprecedented, pushing the health care system to its breaking point. Although significant progress has been made in identifying these highly transmissible variants, what is somewhat lacking is the competence to exploit this information for risk mitigation and effective disease management through an integrated nationwide coordinated approach. With a positivity rate of 15-20% (April-May 2021) and the healthcare system pushed to its limit, accompanied by increased mortality, the situation was rather grim then. Though the central command scrambled all its resources and logistics to streamline the supply chain, the efforts were insufficient in response to the ongoing crisis due to a disproportionate rise in the case. We examined the current scenario emerging from this 2nd COVID wave and identified the possible lacunae. We also suggested few recommendations that may be adopted to avoid similar failures in the future.

Balancing Healthcare and Economy Amidst the COVID-19 Pandemic: An Indian Experience.

With its 1.3 billion population and faced with the COVID-19 pandemic, India is at the junction of two crucial decisions, balancing healthcare and the economy. To prevent the community spread of the virus, the Indian Government imposed a nationwide lockdown. Though initially successful to some extent in containing the disease spread, the extended lockdown eventually leads to a spiraling out effect resulting in the slowdown of the economy, which, in turn, lead to widespread consequences affecting the lives of millions of people, mostly those at the base of the social pyramid. We investigated the implications of few government policies taken during this pandemic and their impact on society, thereby suggesting short-term crisis management with long-term solutions. Here, we present a comprehensive account of Indian policy in dealing with the COVID-19 crisis, balancing both economic and public health. We also explored a future contingency plan for risk mitigation along with few recommendations. This viewpoint will be useful for effective healthcare management and the economy in Asia's populous nation in the COVID-19 and prepare for a future crisis of this nature.

The scars of COVID19: Preparing for the collateral damages

COVID-19 is a pandemic of disproportionate magnitude. Its devastating effect seems to have a more significant impact on the emerging economies like India and the rest of SE Asia, which also has regions harbouring some of the world's highest population density living under poor socio-economic condition. What seems to have originated from one just one province in China, rapidly spread like wildfire across international territories, affecting millions and crippling the health care system. After about eight months into COVID-19, we realized that the fallout is not only humongous but also stretched across multiple avenues of the society and different aspects of our life. The scars of COVID-19 are much more than the virus itself. With a global shutdown in business and financial institutions, the economy is in free fall. Markets plummeted, stocks crashed and unemployment numbers skyrocketed. Apart from the economy, COVID-19 related shutdown has a tremendous impact on the healthcare system for those with preventable ailments, which were either compromised or delayed affecting millions who need hospitalization for non-COVID causes. COVID crisis also seems responsible for the emergence of a new culture system and mindset that was unprecedented before. With schools and other academic institutions closed, online teaching through electronic media and work from home became the new normal. In this editorial, we summarized the collateral damage on society, economy, and human health in the COVID crisis and few suggestions to chalk out a new plan and strategy to address the challenges for a future episode of similar nature. Though we could still remain vulnerable against similar contagious agents, an advanced planning strategy and preparedness will surely help us better in effective damage control and risk mitigation, not only to reduce mortality, but also from economic downfall. [ABSTRACT FROM AUTHOR] Copyright of Asian Journal of Medical Sciences is the property of Manipal Colleges of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)