In silico evaluation of some commercially available terpenoids as spike glycoprotein of SARS-CoV-2 - inhibitors using molecular dynamic approach.

Coronavirus, an extremely contagious infections disease had a harmful effect on the world's population. It is a family of enveloped, single-stranded, positive-strand RNA viruses of Nidovirales order belongs to coroviridae family. At present, worldwide several lakhs of deaths and several billions of infections have been reported. Hence, the focus of the present study was to assess the SARS-CoV-2 enzyme inhibitory potential of certain commercially available terpenoids using Lamarckian genetic algorithm as a working principle and molecular dynamic studies was also performed. AutoDock 4.2 software was used to perform the computational docking calculations of terpenoids against SARS-CoV-2 enzyme. The terpenoids such as, Andrographolide, Betulonic acid, Erythrodiol, Friedelin, Mimuscopic acid, Moronic acid, and Retinol were selected based on the drug likeness properties. Remdesivir a well-known anti-viral drug was selected as the standard drug. Molecular dynamic simulation studies were carried using Desmond module of Schrodinger Suite. In the current study we observed that, Friedelin was exhibited excellent SARS-CoV-2 enzyme inhibitory potential than the standard drug and other selected terpenoids. Friedelin and the standard Remdesivir was undergone the molecular dynamic studies and Friedelin showed a good number of hydrogen bonds over the simulation time of 100 ns. Based on the in silico computational evaluation, it can be concluded that Friedelin could be worthwhile terpenoid against SARS-CoV-2 spike protein. A further study on Friedelin is required to develop a potential chemical entity against the management of COVID disease.Communicated by Ramaswamy H. Sarma.

Antidiabetic Activity of Novel Chromene Compound Isolated from Peperomia Pellucida L. Kunth and in Silico Study against Dpp-Iv, Alpha-Glucosidase, Alpha-Amylase, and Aldose Reductase for Blood Glucose Homeostasis

Objective: During the outbreak of COVID-19, diabetes mellitus (DM) and cardiovascular disease (CVD) become risk factors for severe adverse clinical outcomes in COVID-19 patients. DM is a complex metabolic disease originating from a process of requiring adequate insulin or due to insulin resistance. This in silico study reveals the molecular interaction of Peperochromene A ((S)-2-methyl-2-(4-methylpent-3-enyl)-6-(propan-2-ylidene)-3,4,6,7-tetrahydropyrano[4,3-g]chromen-9(2H)-one), a novel chromene compound isolated from Peperomia pellucida with four proteins involved in the homeostasis of blood glucose, namely dipeptidylpeptidase-IV (DPP-IV), alpha-glucosidase, alpha-amylase, and aldose reductase. Method(s): Molecular docking simulation of the ligands was performed by employing AutoDock 4.2 embedded in LigandScout at a certain position determined automatically by the program. The default parameters of the automatic settings were used to set the genetic algorithm parameters. Result(s): Peperochromene A could interact with all four targets;however, it binds to alpha-glucosidase and alpha-amylase with Ki (inhibition constant) value better than that of acarbose, the enzymes' known inhibitor. This chromene compound also reveals an inhibition constant to aldose reductase similar with that of the enzyme inhibitor. Conclusion(s): The chromene isolated from Peperomia pellucida is the potential to be developed as an inhibitor of the proteins involved in the homeostasis of blood glucose;thus, it can be further explored for its antidiabetic activity. Copyright © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd.

No Change of Pharmacokinetics of Metformin by Concomitant Use of Ensitrelvir

Background. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 diseases. Ensitrelvir exhibited an inhibition potency for organic cation transporter 1 (OCT1) and multidrug and toxin extrusion protein 1 (MATE1) in in vitro study and clinical drug-drug interaction (DDI) study is required judging fromDDI guidance.Metformin is widely used for treatment of diabetes, and is a sensitive substrate for OCT1 and MATE1. We evaluated the effect of ensitrelvir on the pharmacokinetics (PK) ofmetformin with physiologically-based pharmacokinetic (PBPK) modeling and simulation and clinical DDI study. Methods. The PBPK model of ensitrelvir was developed based on the physicochemical parameters, in vitro transporter inhibition parameters, and estimated PK parameters for human. DDI simulations between ensitrelvir and metformin were performed. Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK) was used to develop PBPK model and simulate the DDIs. The in vitro 50% inhibitory concentration (IC50) values of each transporter were used as inhibition constant (Ki) for DDI simulations. Based on the PBPK analysis, the clinical DDI study planed. Results. PBPK analysis: As the result of DDI simulation, ensitrelvir increased the area under the curve (AUC) of metformin by 12%. The result suggests that in vivo DDI potency of ensitrelvir via inhibition of OCT1 or MATE1 would be low at a single dose of ensitrelvir 1000 mg. Clinical DDI study: The plasma concentration-time profile of metformin and ensitrelvir were monitored after 96 hours from a single dose of metformin with or without ensitrelvir. Ensitrelvir does not have effect on the PK of metformin (a geometric mean of AUC ratio was 1.02, Japanese healthy subjects, N=14), suggesting no MATE1 and OCT1 inhibition by ensitrelvir at a clinical dose. The PBPK analysis could well predict the clinical DDI study result. Conclusion. The results of PBPK analysis and the clinical DDI study suggest that no OCT1 and MATE1 inhibition by ensitrelvir is in the clinical dose. Therefore, ensitrelvir does not have a clinically meaningful effect on the pharmacokinetic profile of OCT1 and/or MATE1 substrates including metformin.

In Silico Study of Bioactive Compounds from Sungkai (Peronema Canescens) as Immunomodulator

Objective: This study aims to predict a bioactive compound from Peronema canescens (PC) with mechanisms inhibitor interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) potential as an immunomodulatory using in silico approach. Method(s): Autodock 4 was used to accomplish computer-assisted drug design with molecular docking simulation to discover binding energy, inhibition constant, and interactions with an amino acid in bioactive compounds from PC against IL-6 and TNF-alpha receptors. Lipinski predicts the drug-likeness of a bioactive compound for the oral route of administration. ADMET profiling of bioactive compounds to predict pharmacokinetic properties with pkCSM ADMET. Result(s): The results showed that the best binding energy, inhibition constant, and interactions with an amino acid of peronemin C1 against IL-6 and TNF-alpha receptors were (-7.19 kcal/mol;5.39 nM;Arg 179, Arg 182, Gln 175), and (-8.86 kcal/mol;320.42 nM;Tyr 119, Tyr 59, and Gly 121), respectively. All bioactive compounds from PC met Lipinski's rule of five requirements for oral administration. ADMET prediction results all bioactive compounds from PC are non-mutagenic, except peronemin D1 is mutagenic. Conclusion(s): The peronemin C1 bioactive compounds from PC have good immunomodulatory potential, effectively inhibiting human IL-6 and TNF-alpha receptors using in silico approach. Copyright © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd.

Papain Like Protease: A Potential Target for Middle East Respiratory Syndrome Coronavirus (Mers-Cov): The Battle Continues

Middle-East Respiratory Syndrome coronavirus (MERS-CoV) can trigger severe acute pneumonia, renal, digestive failure and even death. Coronaviruses express papain-like proteases (PLpro), multipurpose enzymes which had protease activity and can lacerate nonstructural proteins to manipulate the viral polyprotein responsible for replication. They also have deubiquitinating function, which can modify the innate immune response. The reduction of the infection of MERS-CoV is by Inhibition of PLpro with a ligand will wedge the cleavage progression of nonstructural protein. As a result, papain-like protease may be considered as a candidate for antiviral drug production. This current study focuses on screening of extracts from Neem and Eucalyptus for MERS-CoV that could be potentially used as an inhibitor against the disease. Blind molecular docking study was conducted by using Auto Dock followed by visualization using PyMol, which is examined in this existing study. Deacetylgedunin (Neem) and eucalyptol (Eucalyptus) showed successful binding to MERS-CoV papain-like protease based on measured parameters such as root Mean Square Deviation (RMSD), binding capacity and inhibiting constant. The compound Deacetylgedunin found in neem exhibited the lowest RMSD value of 16.388 A and the highest binding energy of -8.28 kcal/mol. It also had the highest inhibition constant value of 851.36 nM and the lowest inhibition constant value of 851.36 nM. Since Deacetylgedunin gave a better result compared to Indinavir, hence it can be considered as a potential and safe alternative for the current medicine given for MERS-CoV disease. Copyright All © 2022 are reserved by International Journal of Pharmaceutical Sciences and Research.

PRELIMINARY STUDY FOR COVID-19 DRUG DISCOVERY OF 30 PHYTOCHEMICAL COMPOUNDS FROM TETRAGONULA SP. PROPOLIS AS PAK1 INHIBITOR THROUGH MOLECULAR DOCKING

Objective: This study aims to evaluate 30 phytochemical compounds from Tetragonula sp. propolis as a PAK1 inhibitor using molecular docking. Methods: Thirty propolis compounds were initially confirmed before docking to comply with Lipinski rules. This simulation was performed against PAK1 using AutodockVina, while interaction profile visualization was conducted between the ligand and receptor through Ligplot+and PyMol. Results: Based on the docking score, inhibition constants, and interaction profile analyses, glyurallin B, glyasperin A, and broussoflavonol F were found to be the most potent compounds used as PAK1 inhibitors. According to several literature studies, the propolis compounds were synergistic, leading to adequate collective utilization. Conclusion: These results implicated the potentials of Tetragonula sp. propolis as a therapeutic agent against COVID-19;however, further studies are still needed.

Multi-Targetted Molecular Docking Analysis of Selected Phytoconstituents of Bauhinia acuminata

Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. The study aims to perform Molecular docking analysis of the phytoconstituents of the Bauhinia acuminata named Quercetin, Bauhinone, Beta-sitosterol, and Kaempferol 3-glycoside with the target proteins with PDB IDs namely 2ITY, 1A52, 3L4U, IT02, 5COX, 6VYO involved in Lung cancer, breast cancer, anti-diabetes, anti-obesity, anti-inflammatory, and SARS COV-2. Chemsketch software, the study of the in-silico docking was done using Autodock.4.2 software and the binding interactions are visualized using Discovery studio 3.1. The docking scores and analysis of the interactions of the phytoconstituents with target proteins suggests that all the selected 5 phytoconstituents showed excellent binding to 2ITY and 5-COX as opposed to the standard drugs Erlotinib and Aspirin. In this study, it was concluded that the investigated phytoconstituents showed potent inhibiting activity, and the dock scores as opposed to standard as in Table 6, directly represent possible binding to the target proteins indicating their good biological activity as in lung cancer and anti-inflammatory action.

Probing the Action of Screened Anticancer Triazole–Tetrazole Derivatives Against COVID-19 Using Molecular Docking and DFT Investigations

Drugs are continuously being evaluated for novel therapeutic uses. The purpose of this work was to screen anticancer triazole/tetrazole derivatives for effectiveness against the SARS-CoV-2 main protease (Mpro). First, the chemical structures’ activity was derived from conceptual quantum chemical calculations. According to molecular docking analysis, the compounds scored good interactions against SAR-COV-2's Mpro, with binding energies extending from −8.21 to −8.97 kcal/mol. The docked complexes included various bindings with His41 and Cys145, both catalytic residues responsible for cleavage of the SARS-CoV-2 Mpro. Among the 4 studied compounds, TD3 exhibited the highest affinity by achieving the most stable binding energy and lowest value for the inhibition constant. Most striking was that TD3 not only formed strong bonds with the catalytic residues His41 and Cys145, but also captured the residues of the catalytic loop (Cys44 to Pro52), which flank the catalytic dyads in Mpro's active site. As a result, the studied triazole/tetrazole derivatives, notably TD3, must be reviewed as potent drugs that could be repurposed for SARS-CoV-2 treatment.

Bilastine Based Drugs as SARS-CoV-2 Protease Inhibitors: Molecular Docking, Dynamics, and ADMET Related Studies

Bilastine drugs, structurally piperidine-1-carboxylate and sulfonyloxyethyl carboxylate derivatives, have significantly been employed as the medication of second-generation antihistamine drugs, and are used for the treatment of allergic rhinoconjunctivities and urticarial (hives). The bilastine drugs, composed of benzene carboxylate, propanoate, carboxylate, methyl-sulfonate, propanoic acid, butanoic acid, and pentanoic acid derivatives, were investigated through computational tools against SARS-CoV-2. The COVID-19 virus consists of five proteases where the curial function is performed by main proteases (M-pro) and Spike proteases (S-pro). The M-pro and S-pro were selected for calculation of molecular docking by these bilastine drugs which showed higher binding energy (<-6.5 kcal/mol) for both proteases. The main carboxylic acid group in bilastine drugs is found the primary key for a high binding score to show the large binding affinity with M-pro and S-pro, and is highly responsible for forming the hydrogen bond although the various hydrophobic bonds were produced as a weak interaction. For justification, the stability of molecular docked ligand-protein complexes was investigated with molecular dynamics. It showed that the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of all these drugs were below the 0.9 angstrom after residue interaction. Moreover, the HOMO-LUMO gap, hardness, and softness provided full details for their chemical reactivity. In this view, the pharmacokinetics and Lipinski rule were calculated, and all of these molecules had satisfied the Lipinski rule. Finally, using the admetSAR online database, absorption, distribution, metabolism, excretion, and toxicity have been calculated which indicated that these bilastine drugs are non-carcinogenic and less harmful for both aquatic and non-aquatic species. [GRAPHICS]

Antiviral activity of Matricaria chamomilla in the treatment of COVID-19: Molecular Docking study

Introduction: SARS-CoV-2 infection is a lethal disease caused by a Novel strain of coronaviruses. Although vaccinations of healthy people and meticulous treatment of infected people are the main global health concerns, some plant species have therapeutic effects against viral infections. Matricaria chamomilla is one of the most famous medicinal plants used to manage flu or flu-like symptoms due to its antiviral bioactivity. M. chamomilla belongs to a large group of medicinal herbs used by Persian scholars such as Avicenna and Rhazes to treat respiratory diseases. It has more than 120 chemical constituents, including terpenoids, flavonoids, and some components with potential medicinal activity. In this study, the inhibitory effect of 2 major flavonoid components of M. chamomilla, apigenin and luteolin, was studies for the main protease protein of SARS-CoV-2. Methods: Molecular docking studies were performed using an in-house batch script (DOCKFACE) of Auto Dock 4.2. The 3D structures of the selected flavonoids were retrieved from PubChem, and each ligand was optimized with MM+ then AM1 minimization method using HyperChem 8. The 3D crystal structure of the main protease protein of SARS-CoV-2 (PDB ID: 6LU7) was obtained from the Protein Data Bank (http://www.rcsb.org./pdb). Results: Apigenin and luteolin exhibited good docking scores against 6LU7 receptor, -7.86 and -7.24, respectively, with a combination of hydrogen bonding, van der Waals, and other hydrophobic interactions in the docked complexes. Besides, the estimated inhibition constants, Ki, showed that luteolin exhibited a better inhibitory effect than apigenin. Conclusions: Based on these results, the authors proposed that M. chamomilla can be considered as a valuable resource recommended for preventing SARS-CoV-2 invasion into the human body. Keywords: COVID-19, M. chamomilla, Persian medicine, Molecular Docking, Herbal medicine

Modified D-Glucofuranoses as New Black Fungus Protease Inhibitors: Computational Screening, Docking, Dynamics, and QSAR Study

Notable antimicrobial functionality was found with different sugar esters which were also reported to inhibit the multidrug resistant pathogens along with promising antimicrobial efficacy, and drug-likeness properties. Recent black fungus outbreak, especially in India, along with COVID-19 surmounted the death toll and worsened the conditions severely due to lack of appropriate drugs. Hence, several glucofuranose type esters 4-8 were screened against black fungus related protein (2WTP). These molecules, optimized by DFT, showed good chemical and biological reactivity values especially with pathogens along with satisfactory ADMET profiles. With the good in vitro antifungal activities, these compounds were subjected for molecular docking against the protein of mucormycosis's pathogens, known as black fungus, followed by calculation of inhibition constant, binding energy, and molecular dynamics of the protein-ligand complex. Also, logpIC(50) or pIC(50) was calculated regarding the data for QSAR study. The molecular docking showed that 5-8 had a good binding affinity (> -6.50 kcal mol(-1)) while 7 (-8.00 kcal mol(-1)) and 8 (-8.20 kcal mol(-1)) possessed excellent binding affinity. The inhibition constant and binding energy of the compounds were found very lower among others with stable complexes in 5000 ns in molecular dynamics. Considering all the results, sugar esters 7 and 8 are found to have promising drug properties.

Natural products as LSD1 inhibitors for cancer therapy.

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.