Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2

Since the first cases the coronavirus disease caused by SARS-CoV-2 (COVID-19) reported in December 2019, worldwide continuous efforts have been placed both for the prevention and treatment of this infectious disease. As new variants of the virus emerge, the need for an effective antiviral treatment continues. The concept of preventing SARS-CoV-2 on both pre-entry and post-entry stages has not been much studied. Therefore, we compared the antiviral activities of three antiviral drugs which have been currently used in the clinic. In silico docking analyses and in vitro viral infection in Vero E6 cells were performed to delineate their antiviral effectivity when used alone or in combination. Both in silico and in vitro results suggest that the combinatorial treatment by favipiravir and umifenovir or camostat mesylate has more antiviral activity against SARS-CoV-2 rather than single drug treatment. These results suggest that inhibiting both viral entry and viral replication at the same time is much more effective for the antiviral treatment of SARS-CoV-2.

Molecular Docking, Synthesis, and Tyrosinase Inhibition Activity of Acetophenone Amide: Potential Inhibitor of Melanogenesis

Tyrosinase and its related proteins are responsible for pigmentation disorders, and inhibiting tyrosinase is an established strategy to treat hyperpigmentation. The carbonyl scaffolds can be effective inhibitors of tyrosinase activity, and the fact that both benzoic and cinnamic acids are safe natural substances with such a scaffolded structure, it was speculated that hydroxyl-substituted benzoic and cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. These moieties were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase with a view to explore antimelanogenic ingredients. The most active compound, 2-((3-acetylphenyl)amino)-2-oxoethyl(E)-3-(2,4-dihydroxyphenyl)acrylate (5c), inhibited mushroom tyrosinase with an IC50 of 0.0020 ± 0.0002 μ M , while 2-((3-acetylphenyl)amino)-2-oxoethyl 2,4-dihydroxybenzoate (3c) had an IC50 of 27.35 ± 3.6 μ M in comparison to the positive control arbutin and kojic acid with a tyrosinase inhibitory activity of IC50 of 191.17 ± 5.5 μ M and IC50 of 16.69 ± 2.8 μ M , respectively. Analysis of enzyme kinetics revealed that 5c is a competitive and reversible inhibitor with dissociation constant (Ki) value 0.0072 μM. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the enzymatic pocket for these compounds. The orthohydroxyl of the cinnamic acid moiety of 5c is predicted to form hydrogen bond with the active site side chain carbonyl of Asn 260 (2.16 Å) closer to the catalytic site Cu ions. The acetyl carbonyl is picking up another hydrogen bond with Asn 81 (1.90 Å). The inhibitor 5c passed the panassay interference (PAINS) alerts. This study presents the potential of hydroxyl-substituted benzoic and cinnamic acids and could be beneficial for various cosmetic formulations.

Novel 1,2-thiazine-pyridine hybrid: Design, synthesis, antioxidant activity and molecular docking study

Background & objectives: 1,2-thiazine and pyridine heterocycles drew much attention due to their biological activities including antioxidant activity. Based upon fragment based drug design, novel pyrido[1,2]thiazines 9a-c, thiazolidinopyrido[1,2]thiazines 10a-c and azetidinopyrido[1,2]thiazines 11a-c were designed and prepared. Methods: These novel derivatives 9a-c, 10a-c and 11a-c were subjected to screening for their antioxidant activity via various assays as DPPH radical scavenging potential, reducing power assay and metal chelating potential. Results: All the assayed derivatives exhibited excellent antioxidant potential and the tested compounds 9a, 9b, 10a, 10b, 11a and 11b exhibited higher DPPH scavenging potential (EC50 = 32.7, 53, 36.1, 60, 40.6 and 67 µM, respectively) than ascorbic acid (EC50 = 86.58 µM). While targets 9a, 10a and 11a (RP50 = 52.19, 59.16 and 52.25 µM, respectively) exhibited better reducing power than the ascorbic acid (RP50 = 84.66 µM). Computational analysis had been utilized to prophesy the bioactivity and molecular properties of the target compounds. Conclusion: To predict the binding manner of the novel derivatives as antioxidants, in-silico docking study had been performed to all the newly prepared compounds inside superoxide dismutase (SOD) and catalase (CAT) active site. The most active antioxidant candidate 9a (EC50 = 32.7 µM, RP50 = 52.19 µM) displayed excellent binding with Lys134 amino acid residing at Cu-Zn loop of SOD with binding energy score = -7.54 Kcal/mol thereby increase SOD activity and decrease reactive oxygen species.

In silico Docking Studies of Antiglycation Activity of Isorhamnetin on Molecular Proteins of Advanced Glycation end Product (AGE) Pathway

Advanced glycation end products (AGEs) are formed excessively in pathological conditions due to non - enzymatic glycation of proteins, lipids or nucleic acids, affecting their structure and function. Isorhamnetin is a naturally occurring flavonoid with anti-inflammatory, anti-oxidant, anti-obesity, anticancer, anti-diabetic and anti-atherosclerosis activity. Structure activity studies of isorhamnetin reveal the presence of hydroxyl group in the B-ring of isorhamnetin may contribute to antiglycation activity. Hence we hypothised that isorhamnetin may have antiglycation activity owing to its structure as well as antioxidant and free radical scavenging activities by modulating various AGE pathway proteins. The aim of our study was to determine the antiglycation activity of isorhamnetin by targeting various molecular proteins of AGE pathway using insilico docking. The structure of isorhamnetin was imported and drawn in Marvin sketch (version 6. 3. 0). Nearly 17 molecular proteins of AGE pathway were docked with isorhamnetin using autodock tools 4.2 (version 1. 5. 6) software. The present study showed that isorhamnetin exhibited good docking profiles with receptor for advanced glycation End product (RAGE), protein kinase B (PKB/Akt2), activating transcription factor4 (ATF4), cAMP response element-binding protein (CREB), extracellular signal regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3-K) and signal transducer and activator of transcription (STAT) indicating it may exert good antiglycation activity by modulating these proteins of AGE pathways. However further invitro and invivo studies are required to establish the antiglycation activity of isorhamnetin.

Interaction of Nootropic Drugs with Neurotransmitter Enzyme Acetylcholinesterase: An Insilico Approach: A Review

Nootropic drugs are the class of drugs or supplements that are claimed to enhance cognitive functions, specifically executive functions, memory and creativity in healthy individual. They are sometime referred as cognitive enhancers or smart drugs as they are associated with memory improvement functioning. Some of them are well known drugs and clinically approved by the Food and Drug Administration (FDA). All metabolic reactions are purely dependent on enzymatic actions as they play a very important role in regulating and maintaining most of the biological responses and various processes. An enzyme Acetylcholinesterase (AChE) seems to play an essential role in the conduction of cholinergic brain synapses and neuromuscular junctions. There have been different nootropic drugs identified and approved for curing neurodegenerative disorders such as Alzheimer, Parkinson and Huntington's disease. Their binding efficiency and energy have been well studied an established by using the in-silico docking tools. There are different docking tools available today for analysis of molecules such as PyRx, Auto dock and schrodinger suite. The advent of these tools is being widely used by the pharmaceutical industries for the virtual screening of the formulated drugs against the desired target molecule. It has made the drug formulation process more time efficient and cost effective. Thus, an in-silico approach has been widely accepted for drug discovery and its design.

Therapeutic potential of methylxanthine drug on alpha synuclein protein in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer. It exists in sporadic (90 to 95%) and familial (5 to 10%) form. Its pathogenesis is due to oxidative stress, glutamate excitotoxicity, protein aggregation, neuroinflammation and neurodegeneration. There is currently no cure for this disease. The protein- protein interaction and gene ontology/functional enrichment analysis have been performed to find out the prominent interactor protein and shared common biological pathways, especially PD pathway. Further in silico docking analysis was performed on target protein to investigate the prominent drug molecule for PD. Through computational molecular virtual screening of small molecules from selected twelve natural compounds, and among these compounds methylxanthine was shown to be prominent inhibitor to SNCA protein that ultimately prevent PD. The interaction of methylxanthine compound with the target protein SNCA suggested that, it interacted with prominent binding site with good docking score and might be involved in blocking the binding of neuroinducing substances like: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to SNCA protein. Thus methylxanthine compounds can be explored as promising drugs for the prevention of Parkinson's disease.