Losartan inhibits sars-cov-2 replication in vitro

Purpose: SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus. Methods: The dose-dependent inhibitory effect of losartan, in concentrations from 1μM to 100μM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated.  Results: Losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin.  It was less effective in inhibiting PLpro’s cleavage of ISG15-AMC than Ubiquitin-AMC.  To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%. Conclusion: Losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro.  As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19

Are Losartan and Imatinib Effective Against SARS-CoV2 Pathogenesis? a Pathophysiologic-Based in Silico Study

COVID19 has spread all over the globe with ARDS as the most grave complicating factor in its mortality and morbidity. As there is not an effective anti-viral drug or an imminent vaccine against this virus we proposed a novel insight about cytokine storm-indiced ARDS in this disease and conducted an in silico study according to the pathophysiology of cytokine storm. We found that losartan and imatinib may break the life cycle of the virus to the degree that its affinity to ACE2 may decline, the function of papin-like protease disrupts, and the cytokine storm may subside, as well. This means that the death toll of the disease may decline sharply till a vaccine is produced in the near future. All the results should be validated in subclinical studies.</div

GPCRs of Diverse Physiologic and Pathologic Effects with Fingerprints in COVID-19

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiological functions such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, and neurotransmission as well as in pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of the renin&ndash;angiotensin system (RAS) are members of the GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1&ndash;7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS, including AT1R, AT2R, Mas receptors, and Mas-related GPCR-member D receptor are members of the GPCR family. It is notable that these receptors induce their effects both through G-protein and &beta;-arrestin pathways; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G proteins involved in the adenosine&ndash;CFTR regulation system and epithelial Na-channel function. This article includes a minireview of the physiological functions of GPCRs and their contribution to COVID-19

Synthesis, Molecular Docking, Molecular Dynamics Studies, and Biological Evaluation of 4H-Chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate Derivatives as Potential Antileukemic Agents

A series of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate, and urea or thiourea, using MCM-41-SO3H as efficient nanocatalysts and evaluated for their anticancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP. AutoDock runs resulted in binding energy scores from -7.8 to -10.16 kcal/mol for AutoDock 4 and -6.9 to -8.5 (kcal/mol) for AutoDock Vina. Furthermore, molecular dynamics (MD) simulations are performed using Gromacs for up to 20 ns simulation time investigating the stability of a ligand-protein complex. Finally, a theoretical experiment using MD simulation for 10 ns was performed without defining the initial coordinates, and the affinity binding of ligand to receptors was directly studied, which revealed that the ligand approaches the active sites. The relative free binding energy for the structure 06 (S06), which has the highest binding energy in Autodock 4 and Autodock Vina (-10.10 and -8.5 kcal/mol, respectively), was also evaluated by molecular mechanics (MM) with Poisson-Boltzmann (PB) and a surface area solvation (MM-PBSA) method using g_mmpbsa tools for the last 15 ns MD. On the basis of binding energy scores, a negative binding energy value of 73.6 kcal/mol, S06, was recognized as the dominant potential inhibitors. The cytotoxic properties of S06 was evaluated against three cell lines, acute T cell leukemia (Jurkat), human chronic myelogenous leukemia, (K562) and human foreskin fibroblast (Hu02) using the microculture tetrazolium test MTT assay. Cisplatin was used as the reference agent. The results indicated that S06 has a higher safety index (SI = 0.73, IC50 = 152.64 μg/mL for Jurkat and IC50 = 110.25 μg/mL for Hu02, P < 0.05 means ± SD for four independent experiments) compared to cisplatin (SI = 0.56, IC50 = 8.86 μg/mL for Jurkat and IC50 = 4.96 μg/mL for Hu02). The in silico results indicated that the proposed structures, which have no toxic effects, are potential tyrosine kinase inhibitors (TKIs) that target Bcr-Abl and thus prevent uncontrolled cell growth (proliferation) but not necessarily cell death (apoptosis) and might potentially constitute an interesting novel class of targeted antileukemic drugs, which deserve further studies

Synthesis, Molecular Docking, Molecular Dynamics Studies, and Biological Evaluation of 4<i>H</i>‑Chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate Derivatives as Potential Antileukemic Agents

A series of 4<i>H</i>-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate, and urea or thiourea, using MCM-41-SO₃H as efficient nanocatalysts and evaluated for their anticancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP. AutoDock runs resulted in binding energy scores from −7.8 to −10.16 kcal/mol for AutoDock 4 and −6.9 to −8.5 (kcal/mol) for AutoDock Vina. Furthermore, molecular dynamics (MD) simulations are performed using Gromacs for up to 20 ns simulation time investigating the stability of a ligand–protein complex. Finally, a theoretical experiment using MD simulation for 10 ns was performed without defining the initial coordinates, and the affinity binding of ligand to receptors was directly studied, which revealed that the ligand approaches the active sites. The relative free binding energy for the structure 06 (<b>S06</b>), which has the highest binding energy in Autodock 4 and Autodock Vina (−10.10 and −8.5 kcal/mol, respectively), was also evaluated by molecular mechanics (MM) with Poisson–Boltzmann (PB) and a surface area solvation (MM-PBSA) method using g_mmpbsa tools for the last 15 ns MD. On the basis of binding energy scores, a negative binding energy value of 73.6 kcal/mol, <b>S06</b>, was recognized as the dominant potential inhibitors. The cytotoxic properties of <b>S06</b> was evaluated against three cell lines, acute T cell leukemia (Jurkat), human chronic myelogenous leukemia, (K562) and human foreskin fibroblast (Hu02) using the microculture tetrazolium test MTT assay. Cisplatin was used as the reference agent. The results indicated that <b>S06</b> has a higher safety index (SI = 0.73, IC50 = 152.64 μg/mL for Jurkat and IC50 = 110.25 μg/mL for Hu02, <i>P</i> < 0.05 means ± SD for four independent experiments) compared to cisplatin (SI = 0.56, IC50 = 8.86 μg/mL for Jurkat and IC50 = 4.96 μg/mL for Hu02). The <i>in silico</i> results indicated that the proposed structures, which have no toxic effects, are potential tyrosine kinase inhibitors (TKIs) that target Bcr-Abl and thus prevent uncontrolled cell growth (proliferation) but not necessarily cell death (apoptosis) and might potentially constitute an interesting novel class of targeted antileukemic drugs, which deserve further studies

Environmentally friendly catalyst- and solvent-free synthesis of 2-anilino nicotinic acids derivatives as potential lead COX inhibitors

Abstract In this study, an environmentally friendly, solvent- and catalyst-free synthesis of 2-anilino nicotinic acids derivatives is reported. This operationally simple and green procedure was applied to a selection of primary aromatic amines giving rise to 23 derivatives of 2-anilino nicotinic acids in a very short reaction time (15–120 min) with good to excellent yield. Next, similarity searches were executed on these derivatives to find the possible biological target. These products were screened for inhibition of COX-1 and COX-2 by molecular docking and dynamic studies. In silico studies revealed that among these derivatives, the structure 10 bearing meta-chlorine substitutions could act as COX-1 and COX-2 inhibitors. These results can be used in designing important lead compounds for further development as potential anti-inflammatory drugs