Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2.

A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme.Communicated by Ramaswamy H. SarmaHighlightsQuinoline derivatives have been designed as protease inhibitors against SARS-CoV-2.The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex.Docking studies indicated the stable ligand-protein complexes for all designed compounds.The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives.Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.

COVID-19: Pathophysiology, Transmission, and Drug Development for Therapeutic Treatment and Vaccination Strategies.

COVID-19, a dreaded and highly contagious pandemic, is flagrantly known for its rapid prevalence across the world. Till date, none of the treatments are distinctly accessible for this life-threatening disease. Under the prevailing conditions of a medical emergency, one creative strategy for the identification of novel and potential antiviral agents gaining momentum in research institutions and progressively being leveraged by pharmaceutical companies is target-based drug repositioning/repurposing. Continuous monitoring and recording of results offer anticipation that this strategy may help to reveal new medications for viral infections. This review recapitulates the neoteric illation of COVID-19, its genomic dispensation, molecular evolution via phylogenetic assessment, drug targets, the most frequently worldwide used repurposed drugs and their therapeutic applications, and a recent update on vaccine management strategies. The available data from solidarity trials exposed that the treatment with several known drugs, viz. lopinavir-ritonavir, chloroquine, hydroxychloroquine, etc. had displayed various antagonistic effects along with no impactful result in the diminution of mortality rate. The drugs, like remdesivir, favipiravir, and ribavirin, have proved to be quite safer therapeutic options for treatment against COVID-19. Similarly, dexamethasone, convalescent plasma therapy and oral administration of 2DG are expected to reduce the mortality rate of COVID-19 patients.

Binding of raloxifene to human complement fragment 5a (hC5a): a perspective on cytokine storm and COVID19.

Human C5a (hC5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection. hC5a has been associated with the pathogenesis of many chronic and acute diseases, due to its proven ability in triggering the 'cytokine storm', by binding to its cognate receptor C5aR, expressed in myriad of tissues. Given the pleiotropic downstream function of hC5a, it is logical to consider the hC5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive hC5a, by implementing the repurposing strategies for FDA-approved drugs. Indeed, the proof of principle biophysical studies published recently is encouraging, which strongly supports the potential of this strategy. Considering BSA-carprofen as a reference model system, the current study further explores the inherent conformational plasticity of hC5a and its effect in accommodating more than one drug molecule cooperatively at multiple sites. The data generated by recruiting a battery of experimental and computational biology techniques strongly suggest that hC5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki ∼ 0.5 µM and Ki ∼ 3.58 µM on its surface at non-analogous sites. The study hints at exploration of polypharmacology approach, as a new avenue for discovering synergistic drug molecule pairs, or drug molecules with 'broad-range' binding affinity for targeting the different 'hot spots' on hC5a, as an alternative combination therapy for possible management of the 'cytokine storm'-related inflammatory diseases, like COVID19.Communicated by Ramaswamy H. Sarma.

Breathability and Safety Testing of Personal Protective Equipment: "Human-comfort" Factor Remains Undefined.

Healthcare systems all over the world have been enormously affected by the COVID-19 pandemic. Healthcare workers (HCWs) taking care of these patients need personal protective equipments (PPEs) standardized for full protection from droplets and aerosols carrying viral load to variable distances. There has been a surge of manufacturers supplying these protective gears in India and regulatory agencies have issued technical specifications pertaining to PPEs focusing solely on synthetic blood penetration tests (SBPTs) and keeping the upper limit of non-woven fabric to 95 g/m2 (GSM). These PPE specifications are silent on air permeability (AP) and water/moisture vapor transmission rate (WVTR/MVTR) of the fabric. As a result, most of the PPE kits, despite having appropriate SBPT certifications from regulatory agencies, have extremely poor permeability and breathability. The acceptability of PPEs by HCWs can be vastly improved when the end-users are proactively invited to participate in "comfort testing" of PPEs before getting issuance of certification for marketing. "Field testing" or "end-user trials" in which HCWs don the PPE and assess it for comfort while performing different types of clinical work, e.g., in intensive care units (ICUs), operation theaters, cath labs, etc., also takes into account a hitherto often ignored "human-comfort-factor" that not only enhances the understanding of HCWs about the need for the PPEs but can also motivate them to use it without worrying about discomfort. We hereby propose that comfort fit testing (COmfort and Material Fit is an Obviously Required Test) should be a part of the mandatory testing and certification process for PPE, so that the industry invests wisely in manufacturing PPE kits that are not only certified for fabric but are also tested for comfort factors. How to cite this article: Kapoor A, Baronia AK, Azim A, Agarwal G, Prasad N, Mishra R, et al. Breathability and Safety Testing of Personal Protective Equipment: "Human-comfort" Factor Remains Undefined. Indian J Crit Care Med 2021;25(1):12-15.