Identification of potential inhibitors of SARS-CoV-2 main protease and spike receptor from 10 important spices through structure-based virtual screening and molecular dynamic study.
ABSTRACT: The outbreak of novel coronavirus disease (COVID-19) caused by SARS-CoV-2 poses a serious threat to human health and world economic activity. There is no specific drug for the treatment of COVID-19 patients at this moment. Traditionally, people have been using spices like ginger, fenugreek and onion, etc. for the remedy of a common cold. This work identifies the potential inhibitors of the main protease (Mpro) and spike (S) receptor of SARS-CoV-2 from 10 readily available spices. These two proteins, S and Mpro, play an important role during the virus entry into the host cell, and replication and transcription processes of the virus, respectively. To identify potential molecules an in-house databank containing 1040 compounds was built-up from the selected spices. Structure-based virtual screening of this databank was performed with two important SARS-CoV-2 proteins using Glide. Top hits resulted from virtual screening (VS) were subjected to molecular docking using AutoDock 4.2 and AutoDock Vina to eliminate false positives. The top six hits against Mpro and top five hits against spike receptor subjected to 130 ns molecular dynamic simulation using GROMACS. Finally, the compound 1-, 2-, 3- and 5-Mpro complexes, and compound 17-, 18-, 19-, 20- and 21- spike receptor complexes showed stability throughout the simulation time. The ADME values also supported the drug-like nature of the selected hits. These nine compounds are available in onion, garlic, ginger, peppermint, chili and fenugreek. All the spices are edible and might be used as home remedies against COVID-19 after proper biological evaluation.
Project description:Colorectal cancer (CRC) is the second most deadly cancer worldwide. CRC management is challenging due to late detection, high recurrence rate, and multi-drug resistance. Herbs and spices used in cooking, practised for generations, have been shown to contain CRC protective effect or even be useful as an anti-CRC adjuvant therapy when used in high doses. Herbs and spices contain many bioactive compounds and possess many beneficial health effects. The chemopreventive properties of these herbs and spices are mainly mediated by the BCL-2, K-ras, and MMP pathways, caspase activation, the extrinsic apoptotic pathway, and the regulation of ER-stress-induced apoptosis. As a safer natural alternative, these herbs and spices could be good candidates for chemopreventive or chemotherapeutic agents for CRC management because of their antiproliferative action on colorectal carcinoma cells and inhibitory activity on angiogenesis. Therefore, in this narrative review, six different spices and herbs: ginger (Zingiber officinale Roscoe), turmeric (Curcuma longa L.), garlic (Allium sativum L.), fenugreek (Trigonella foenum-graecum L.), sesame (Sesamum indicum L.), and flaxseed (Linum usitatissimum L.) used in daily cuisine were selected for this study and analyzed for their chemoprotective or chemotherapeutic roles in CRC management with underlying molecular mechanisms of actions. Initially, this study comprehensively discussed the molecular basis of CRC development, followed by culinary and traditional uses, current scientific research, and publications of selected herbs and spices on cancers. Lead compounds have been discussed comprehensively for each herb and spice, including anti-CRC phytoconstituents, antioxidant activities, anti-inflammatory properties, and finally, anti-CRC effects with treatment mechanisms. Future possible works have been suggested where applicable.
Project description:Culinary herbs and spices have been used as both food flavoring and food preservative agents for centuries. Moreover, due to their known and presumptive health benefits, herbs and spices have also been used in medical practices since ancient times. Some of the health effects attributed to herbs and spices include antioxidant, anti-microbial, and anti-inflammatory effects as well as potential protection against cardiovascular disease, neurodegeneration, type 2 diabetes, and cancer. While interest in herbs and spices as medicinal agents remains high and their use in foods continues to grow, there have been remarkably few studies that have attempted to track the dietary intake of herbs and spices and even fewer that have tried to find potential biomarkers of food intake (BFIs). The aim of the present review is to systematically survey the global literature on herbs and spices in an effort to identify and evaluate specific intake biomarkers for a representative set of common herbs and spices in humans. A total of 25 herbs and spices were initially chosen, including anise, basil, black pepper, caraway, chili pepper, cinnamon, clove, cumin, curcumin, dill, fennel, fenugreek, ginger, lemongrass, marjoram, nutmeg, oregano, parsley, peppermint and spearmint, rosemary, saffron, sage, tarragon, and thyme. However, only 17 of these herbs and spices had published, peer-reviewed studies describing potential biomarkers of intake. In many studies, the herb or spice of interest was administrated in the form of a capsule or extract and very few studies were performed with actual foods. A systematic assessment of the candidate biomarkers was also performed. Given the limitations in the experimental designs for many of the published studies, further work is needed to better evaluate the identified set of BFIs. Although the daily intake of herbs and spices is very low compared to most other foods, this important set of food seasoning agents should not be underestimated, especially given their potential benefits to human health.
Project description:Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.
Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a virus that causes the infectious disease coronavirus disease-2019. Currently, there is no effective drug for the prevention and treatment of this virus. This study aimed to identify secondary metabolites that potentially inhibit the key proteins of SARS-CoV-2. This was an <i>in silico</i> molecular docking study of several secondary metabolites of Indonesian herbal plant compounds and other metabolites with antiviral testing history. Virtual screening using AutoDock Vina of 216 Lipinski rule-compliant plant metabolites was performed on 3C-like protease (3CL<sup>pro</sup>), RNA-dependent RNA polymerase (RdRp), and spike glycoprotein. Ligand preparation was performed using JChem and Schrödinger's software, and virtual protein elucidation was performed using AutoDockTools version 1.5.6. Virtual screening identified several RdRp, spike, and 3CL<sup>pro</sup> inhibitors. Justicidin D had binding affinities of -8.7, -8.1, and -7.6 kcal mol<sup>-1</sup> on RdRp, 3CL<sup>pro</sup>, and spike, respectively. 10-methoxycamptothecin had binding affinities of -8.5 and -8.2 kcal mol<sup>-1</sup> on RdRp and spike, respectively. Inoxanthone had binding affinities of -8.3 and -8.1 kcal mol<sup>-1</sup> on RdRp and spike, respectively, while binding affinities of caribine were -9.0 and -7.5 mol<sup>-1</sup> on 3CL<sup>pro</sup> and spike, respectively. Secondary metabolites of compounds from several plants were identified as potential agents for SARS-CoV-2 therapy.
Project description:The novel coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) or COVID-19 has caused a worldwide pandemic. The fatal virus has affected the health of human beings as well as the socio-economic situation all over the world. To date, no concrete medicinal solution has been proposed to combat the viral infection, calling for an urgent, strategic, and cost-effective drug development approach that may be achievable by applying targeted computational and virtual screening protocols. Immunity is the body's natural defense against disease-causing pathogens, which can be boosted by consuming plant-based or natural food products. Active constituents derived from natural sources also scavenge the free radicals and have anti-inflammatory activities. Herbs and spices have been used for various medicinal purposes. In this study, 2,96 365 natural and synthetic derivatives (ligands) belonging to 102 classes of compounds were obtained from PubChem and assessed on Lipinski's parameters for their potential bioavailability. Out of all the derivatives, 3254 obeyed Lipinski's rule and were virtually screened. The 115 top derivatives were docked against SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-HKV1 main proteases (M<sup>pro</sup> s) as receptors using AutoDock Vina, AutoDock, and iGEMDOCK 2.1. The lowest binding energy was exhibited by ligands 2 and 6 against all the four M<sup>pro</sup> s. The molecular dynamic simulation was also performed with ligand 6 using the GROMACS package. Good bioactivity scores, absorption, distribution, metabolism, excretion, and toxicity profile and drug-like pharmacokinetic parameters were also obtained. Hydroxychloroquine was used as the control drug.
Project description:The outbreak of respiratory disease, COVID-19 caused by SARS-CoV-2 has now been spread globally and the number of new infections is rising every moment. There are no specific medications that are currently available to combat the disease. The spike receptor of SARS-CoV-2 facilitates the viral entry into a host cell and initiation of infection. Targeting the viral entry at the initial stage has a better advantage than inhibiting it in later stages of the viral life cycle. This study deals with identification of the potential natural molecule or its derivatives from MolPort Databank as SARS-CoV-2 spike receptor inhibitors using structure-based virtual screening followed by molecular dynamics simulation. On the basis of ADME properties, docking score, MMGBSAbinding energy, 150 ns molecular docking studies, and final molecular dynamics analysis, two natural compounds - <b>3</b> (MolPort-002-535-004) docking score -9.10 kcal mol-1 and <b>4</b> (MolPort-005-910-183) docking score -8.5 kcal mol<sup>-1</sup>, are selected as potential in-silico spike receptor inhibitors. Both hits are commercially available and can be further used for <i>in-vitro</i> and <i>in-vivo</i> studies. Findings of this study can facilitate rational drug design against SARS-CoV-2 spike receptor.
Project description:<b>Aim:</b> Virus spike glycoprotein of SARS-CoV-2 is a good target for drug discovery. <b>Objective:</b> To examine the potential for druggability of spike protein for pharmacophore-based drug discovery and to investigate the binding affinity of natural products with SARS-CoV-2 spike protein. <b>Methods:</b> Druggable cavities were searched though CavityPlus. A pharmacophore was built and used for hit identification. Autodock Vina was used to evaluate the hits' affinities. 10 chemical derivatives were also made from the chemical backbone to optimize the lead compound. <b>Results:</b> 10 druggable cavities were found within the glycoprotein spike. Only one cavity with the highest score at the binding site was selected for pharmacophore extraction. Hit identification resulted in the identification of 410 hits. <b>Discussion:</b> This study provides a druggable region within viral glycoprotein and a candidate compound to block viral entry.
Project description:The main protease (M<sup>pro</sup>) of SARS-CoV-2 is an appealing target for the development of antiviral compounds, due to its critical role in the viral life cycle and its high conservation among different coronaviruses and the continuously emerging mutants of SARS-CoV-2. Ferulic acid (FA) is a phytochemical with several health benefits that is abundant in plant biomass and has been used as a basis for the enzymatic or chemical synthesis of derivatives with improved properties, including antiviral activity against a range of viruses. This study tested 54 reported FA derivatives for their inhibitory potential against M<sup>pro</sup> by in silico simulations. Molecular docking was performed using Autodock Vina, resulting in comparable or better binding affinities for 14 compounds compared to the known inhibitors N3 and GC376. ADMET analysis showed limited bioavailability but significantly improved the solubility for the enzymatically synthesized hits while better bioavailability and druglikeness properties but higher toxicity were observed for the chemically synthesized ones. MD simulations confirmed the stability of the complexes of the most promising compounds with M<sup>pro</sup>, highlighting FA rutinoside and compound e27 as the best candidates from each derivative category.
Project description:Culinary herbs and spices are widely used as a traditional medicine in the treatment of diabetes and its complications, and there are several scientific studies in the literature supporting the use of these medicinal plants. However, there is often a lack of knowledge on the bioactive compounds of these herbs and spices and their mechanisms of action. The aim of this study was to use inverse virtual screening to provide insights into the bioactive compounds of common herbs and spices, and their potential molecular mechanisms of action in the treatment of diabetes. In this study, a library of over 2300 compounds derived from 30 common herbs and spices were screened in silico with the DIA-DB web server against 18 known diabetes drug targets. Over 900 compounds from the herbs and spices library were observed to have potential anti-diabetic activity and liquorice, hops, fennel, rosemary, and fenugreek were observed to be particularly enriched with potential anti-diabetic compounds. A large percentage of the compounds were observed to be potential polypharmacological agents regulating three or more anti-diabetic drug targets and included compounds such as achillin B from yarrow, asparasaponin I from fenugreek, bisdemethoxycurcumin from turmeric, carlinoside from lemongrass, cinnamtannin B1 from cinnamon, crocin from saffron and glabridin from liquorice. The major targets identified for the herbs and spices compounds were dipeptidyl peptidase-4 (DPP4), intestinal maltase-glucoamylase (MGAM), liver receptor homolog-1 (NR5A2), pancreatic alpha-amylase (AM2A), peroxisome proliferator-activated receptor alpha (PPARA), protein tyrosine phosphatase non-receptor type 9 (PTPN9), and retinol binding protein-4 (RBP4) with over 250 compounds observed to be potential inhibitors of these particular protein targets. Only bay leaves, liquorice and thyme were found to contain compounds that could potentially regulate all 18 protein targets followed by black pepper, cumin, dill, hops and marjoram with 17 protein targets. In most cases more than one compound within a given plant could potentially regulate a particular protein target. It was observed that through this multi-compound-multi target regulation of these specific protein targets that the major anti-diabetic effects of reduced hyperglycemia and hyperlipidemia of the herbs and spices could be explained. The results of this study, taken together with the known scientific literature, indicated that the anti-diabetic potential of common culinary herbs and spices was the result of the collective action of more than one bioactive compound regulating and restoring several dysregulated and interconnected diabetic biological processes.
Project description:The ginger family (<i>Zingiberaceae</i>) includes plants that are known worldwide to have a distinctive smell and taste, which are often used as spices in the kitchen, but also in various industries (pharmaceutical, medical, and cosmetic) due to their proven biological activity. The aim of this study was to investigate and compare the chemical composition and antioxidant activity (AA) of essential oils (EOs) of four characteristic ginger species: <i>Elettaria cardamomum</i> L. Maton (cardamom), <i>Curcuma Longa</i> L. (turmeric), <i>Zingiber Officinale</i> Roscoe (ginger), and <i>Alpinia Officinarum</i> Hance (galangal). Furthermore, the total phenolic content (TPC) and AA of crude extracts obtained after using ultrasound-assisted extraction (UAE) and different extraction solvents (80% ethanol, 80% methanol and water) were evaluated. A total of 87 different chemical components were determined by GC-MS/MS in the EOs obtained after hydrodistillation, 14 of which were identified in varying amounts in all EOs. The major compounds found in cardamom, turmeric, ginger, and galangal were α-terpinyl acetate (40.70%), β-turmerone (25.77%), α-zingiberene (22.69%) and 1,8-cineol (42.71%), respectively. In general, 80% ethanol was found to be the most effective extracting solvent for the bioactivities of the investigated species from the <i>Zingiberaceae</i> family. Among the crude extracts, ethanolic extract of galangal showed the highest TPC value (63.01 ± 1.06 mg GA g<sup>-1</sup> DW), while the lowest TPC content was found in cardamom water extract (1.04 ± 0.29 mg GA g<sup>-1</sup> DW). The AA evaluated by two different assays (ferric-reducing antioxidant power-FRAP and the scavenging activity of the cationic ABTS radical) proved that galangal rhizome is the plant with the highest antioxidant potential. In addition, no statistical difference was found between the AA of turmeric and ginger extracts, while cardamom rhizome was again inferior. In contrast to the crude extracts, the EOs resulted in significantly lower ABTS and FRAP values, with turmeric EO showing the highest AA.