Possibility of HIV-1 protease inhibitors-clinical trial drugs as repurposed drugs for SARS-CoV-2 main protease: a molecular docking, molecular dynamics and binding free energy simulation study.

Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome the COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs against HIV-1 protease namely, TMB607 and TMC310911 to use as the inhibitors of SARS-CoV-2 main protease (Mpro) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of the binding mechanism of these two molecules with the SARS-CoV-2 Mpro. To understand the binding mechanism, we have performed molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations against the SARS-CoV-2 Mpro. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of Mpro enzyme. However, during the MD simulations, TMB607 forms strong interaction with the key amino acids of Mpro, and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This in silico study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 Mpro enzyme and it may be suitable for the drug repurposing of COVID-19 and further drug designing.Communicated by Ramaswamy H. Sarma.

Novel antioxidant astaxanthin-s-allyl cysteine biconjugate diminished oxidative stress and mitochondrial dysfunction to triumph diabetes in rat model.

AIMS: The present study determines the effect of administration of novel antioxidant astaxanthin-s-allyl cysteine biconjugate (AST-SAC) against streptozotocin-induced diabetes mellitus (DM) in rats. MAIN METHODS: AST-SAC (1 mg/kg/day) was treated against DM in rats for 45 days. The oxidative stress, antioxidants level, insulin secretion, activities of various carbohydrate metabolizing enzymes were studied. The glucose uptake in L6 myotubes was studied. In addition, in silico analysis of interaction of AST-SAC with proteins such as insulin receptor (IR) and 5'-adenosine monophosphate-activated protein kinase (AMPK) were carried out. KEY FINDINGS: Administration of AST-SAC in DM rats has protected the mitochondrial function (decreased oxidative stress and normalized oxidative phosphorylation activities) and antioxidant capacity of the pancreas which has resulted in beta cells rejuvenation and insulin secretion restoration. AST-SAC decreased the alpha-glucosidases activities to bring glycemic control in DM rats. Due to these effects the glycoprotein components and lipids were restored to near normalcy in DM rats. AST-SAC protected the antioxidant status of liver, kidney and plasma; and curbed the progression of secondary complications of DM. AST-SAC treatment stimulated glucose uptake in L6 myotubes in in vitro. To support this observation, AST-SAC interacted with proteins such as IR and AMPK in silico. SIGNIFICANCE: AST-SAC can be considered as "multi-target-directed ligand", that is, through these manifold effects, AST-SAC has been able to prevail over DM in rats.

New amino acid-Schiff base derived from s-allyl cysteine and methionine alleviates carbon tetrachloride-induced liver dysfunction.

In spite of the tremendous stride in modern medicine, conventional drugs used in the hepatotoxic management are mostly inadequate. The present study aims in the synthesis of novel Schiff base compound derived using s-allyl cystiene and methionine. The newly synthesized compound, 2-((2-((2-(allylthio)-1-carboxyethyl)imino)ethylidene)amino)-4-(methylthio)butanoic acid (ACEMB) was characterized using UV-visible spectrophotometer, FTIR, 1HNMR, and GC-MS. ACEMB showed potent in vitro antioxidant property. Chronic administration of ACEMB prior to CCl4 intoxication: i) attenuated the leakage of liver injury markers, such as, enzymes (AST, ALT, GGT, ALP and LDH) and biomolecules (bilirubin) into the blood circulation; ii) normalized the concentration of total proteins, albumin and globulin to control level; and iii) protected the liver against dyslipidemia. These effects of ACEMB show the preservation of endoplasmic reticulum function against CCl4 toxicity in the liver. The protective effect of ACEMB was due to its antioxidant property, which was revealed by reduced oxidative stress (TBARS and HP) and enhanced functions of the endogenous antioxidative system (SOD, catalase, GPx, GST, GSH, vitamin E and C) against CCl4 intoxication. Also, ACEMB protected the functional activities of the various mitochondrial tricarboxylic acid cycle and oxidative phosphorylation enzymes. The biochemical alterations are in concurrence with the histological observations, wherein ACEMB pretreatment prevented the vacuolation, degeneration of nuclei and necrosis of hepatocytes. In addition, in silico analysis reveals the interaction of ACEMB in the active site of cytochrome P450. ACEMB mediates hepatoprotective effect by substituting itself as an antioxidant and decreasing oxidative stress, thereby diminishing the intracellular organelle dysfunction against CCl4 toxicity in the liver.