Molecular docking identification of plant-derived inhibitors   of the COVID-19 main protease

AbstractMpro is of considerable interest as a drug target in the treatment of COVID-19 since the proteolytic activity of this viral protease is essential for viral replication. Here we report the first insight of the structure Mpro for SARS-CoV-2 in the inactive conformation under conditions close to the physiological state (pH 7.5) to an overall resolution of 1.9 Å. The comparisons of Mpro in different states reveal that substrate binding site and the active site are more flexible in the inactive conformation than that in the active conformations. Notably, compared with the active conformation of the apo state structure in pH7.6 of SARS, the SARS-CoV-2 apo state is in the inactive conformation under condition close to physiological state (pH7.5). Two water molecules are present in the oxyanion hole in our apo state structure, whereas in the ligand-bound structure, water molecular is absence in the same region. This structure provides novel and important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational, structure-based, approaches for the design of specific SARS-CoV-2 ligands as new therapeutic agents.

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Identification of Potent COVID-19 Main Protease (Mpro) Inhibitors from Natural Polyphenols: An in Silico Strategy Unveils a Hope against CORONA

10.20944/preprints202003.0333.v1 ◽

2020 ◽

Cited By ~ 28

Author(s):

Sevki Adem ◽

Volkan Eyupoglu ◽

Iqra Sarfraz ◽

Azhar Rasul ◽

Muhammad Ali

Keyword(s):

Molecular Docking ◽

Drug Target ◽

Docking Study ◽

Binding Energies ◽

Therapeutic Drug ◽

Molecular Docking Study ◽

Molegro Virtual Docker ◽

Main Protease ◽

Chinese Researcher ◽

Native Ligand

COVID-19, a rapidly spreading new strain of coronavirus, has affected more than 150 countries and received worldwide attention. The lack of efficacious drugs or vaccines against SARS-CoV-2 has further worsened the situation. Thus, there is an urgent need to boost up research for the development of effective therapeutics and affordable diagnostic against COVID-19. The crystallized form of SARS-CoV-2 main protease (Mpro) was demonstrated by a Chinese researcher Liu et al. (2020) which is a novel therapeutic drug target. This study was conducted to evaluate the efficacy of medicinal plant-based bioactive compounds against COVID-19 Mpro by molecular docking study. Molecular docking investigations were performed by using Molegro Virtual Docker 7 to analyze the inhibition probability of these compounds against COVID-19. COVID-19 Mpro was docked with 80 flavonoid compounds and the binding energies were obtained from the docking of (PDB ID: 6LU7: Resolution 2.16 Å) with the native ligand. According to obtained results, hesperidin, rutin, diosmin, apiin, diacetylcurcumin, (E)-1-(2-Hydroxy-4-methoxyphenyl)-3-[3-[(E)-3-(2-hydroxy-4- methoxyphenyl)-3-oxoprop-1-enyl]phenyl]prop-2-en-1-one, and beta,beta'-(4-Methoxy-1,3- phenylene)bis(2'-hydroxy-4',6'-dimethoxyacrylophenone have been found as more effective on COVID-19 than nelfinavir. So, this study will pave a way for doing advanced experimental research to evaluate the real medicinal potential of these compounds to cure COVID-19.

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Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

10.26434/chemrxiv.13118117 ◽

2020 ◽

Author(s):

Maria Antonela Zigolo ◽

Matías Rivero Goytia ◽

Hugo Ramiro Poma ◽

Verónica Rajal ◽

Veronica Patricia Irazusta

Keyword(s):

Hydrophobic Interactions ◽

Viral Proteins ◽

Natural Compounds ◽

Docking Studies ◽

Binding Energies ◽

Host Cells ◽

Computational Tools ◽

S Protein ◽

Synthetic Drugs ◽

Main Protease

The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease Mpro, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For Mpro were, in kcal/mol: -9.36 for spirostan, -8.75 for N-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for Mpro. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19.

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Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

10.26434/chemrxiv.13118117.v1 ◽

2020 ◽

Author(s):

Maria Antonela Zigolo ◽

Matías Rivero Goytia ◽

Hugo Ramiro Poma ◽

Verónica Rajal ◽

Veronica Patricia Irazusta

Keyword(s):

Hydrophobic Interactions ◽

Viral Proteins ◽

Natural Compounds ◽

Docking Studies ◽

Binding Energies ◽

Host Cells ◽

Computational Tools ◽

S Protein ◽

Synthetic Drugs ◽

Main Protease

The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease Mpro, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For Mpro were, in kcal/mol: -9.36 for spirostan, -8.75 for N-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for Mpro. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19.

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Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

Current Pharmaceutical Design ◽

10.2174/1381612825666190716114056 ◽

2019 ◽

Vol 25 (25) ◽

pp. 2772-2787 ◽

Cited By ~ 6

Author(s):

Raghu P. Mailavaram ◽

Omar H.A. Al-Attraqchi ◽

Supratik Kar ◽

Shinjita Ghosh

Keyword(s):

Drug Target ◽

Therapeutic Agents ◽

G Protein Coupled Receptors ◽

Current Status ◽

Renal Diseases ◽

Adenosine A3 Receptor ◽

Drug Candidates ◽

Novel Drugs ◽

The Family ◽

G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

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Possible Targets and Therapies of SARS-CoV-2 Infection

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200807131855 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1900-1907

Author(s):

Kasturi Sarkar ◽

Parames C. Sil ◽

Seyed Fazel Nabavi ◽

Ioana Berindan-Neagoe ◽

Cosmin Andrei Cismaru ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Viral Replication ◽

Viral Infection ◽

Human Activity ◽

Viral Proteins ◽

Therapeutic Agents ◽

Effective Control ◽

Human Society ◽

Global Spread ◽

Repurposed Drugs

The global spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes COVID-19 has become a source of grave medical and socioeconomic concern to human society. Since its first appearance in the Wuhan region of China in December 2019, the most effective measures of managing the spread of SARS-CoV-2 infection have been social distancing and lockdown of human activity; the level of which has not been seen in our generations. Effective control of the viral infection and COVID-19 will ultimately depend on the development of either a vaccine or therapeutic agents. This article highlights the progresses made so far in these strategies by assessing key targets associated with the viral replication cycle. The key viral proteins and enzymes that could be targeted by new and repurposed drugs are discussed.

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Natural Compounds and Drug Discovery: Can Cnidarian Venom Play a Role?

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666190227234834 ◽

2019 ◽

Vol 19 (2) ◽

pp. 114-118

Author(s):

Gian Luigi Mariottini ◽

Irwin Darren Grice

Keyword(s):

Biological Activity ◽

Marine Species ◽

Natural Compounds ◽

Therapeutic Agents ◽

Industrial Applications ◽

Bioactive Molecules ◽

Sea Anemones ◽

Therapeutic Approaches ◽

Ongoing Research ◽

Biological Compounds

Natural compounds extracted from organisms and microorganisms are an important resource for the development of drugs and bioactive molecules. Many such compounds have made valuable contributions in diverse fields such as human health, pharmaceutics and industrial applications. Presently, however, research on investigating natural compounds from marine organisms is scarce. This is somewhat surprising considering that the marine environment makes a major contribution to Earth's ecosystems and consequently possesses a vast storehouse of diverse marine species. Interestingly, of the marine bioactive natural compounds identified to date, many are venoms, coming from Cnidarians (jellyfish, sea anemones, corals). Cnidarians are therefore particularly interesting marine species, producing important biological compounds that warrant further investigation for their development as possible therapeutic agents. From an experimental aspect, this review aims to emphasize and update the current scientific knowledge reported on selected biological activity (antiinflammatory, antimicrobial, antitumoral, anticoagulant, along with several less studied effects) of Cnidarian venoms/extracts, highlighting potential aspects for ongoing research towards their utilization in human therapeutic approaches.

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Phytochemicals and Biological Activity of Desert Date (Balanites aegyptiaca (L.) Delile)

Plants ◽

10.3390/plants10010032 ◽

2020 ◽

Vol 10 (1) ◽

pp. 32

Author(s):

Hosakatte Niranjana Murthy ◽

Guggalada Govardhana Yadav ◽

Yaser Hassan Dewir ◽

Abdullah Ibrahim

Keyword(s):

Biological Activity ◽

Middle East ◽

Bioactive Compounds ◽

Phenolic Acids ◽

Tree Species ◽

Indian Subcontinent ◽

Therapeutic Agents ◽

Root Bark ◽

Balanites Aegyptiaca ◽

Anti Inflammatory

Many underutilized tree species are good sources of food, fodder and possible therapeutic agents. Balanites aegyptiaca (L.) Delile belongs to the Zygophyllaceae family and is popularly known as “desert date”, reflecting its edible fruits. This tree grows naturally in Africa, the Middle East and the Indian subcontinent. Local inhabitants use fruits, leaves, roots, stem and root bark of the species for the treatment of various ailments. Several research studies demonstrate that extracts and phytochemicals isolated from desert date display antioxidant, anticancer, antidiabetic, anti-inflammatory, antimicrobial, hepatoprotective and molluscicidal activities. Mesocarp of fruits, seeds, leaves, stem and root bark are rich sources of saponins. These tissues are also rich in phenolic acids, flavonoids, coumarins, alkaloids and polysterols. Some constituents show antioxidant, anticancer and antidiabetic properties. The objective of this review is to summarize studies on diverse bioactive compounds and the beneficial properties of B. aegyptiaca.

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Development of Web Application for the Comparison of Segment Variability with Sequence Evolution and Immunogenic Properties for Highly Variable Proteins: An Application to Viruses

10.1101/2021.12.01.470810 ◽

2021 ◽

Author(s):

Sumit Bala ◽

Ambarnil Ghosh ◽

Subhra Pradhan

Keyword(s):

Experimental Research ◽

Web Application ◽

Structural Information ◽

Solvent Accessibility ◽

Viral Proteins ◽

High Rate ◽

Survival Strategies ◽

Host Immune System ◽

Application Development ◽

The Web

AbstractHigh rate of mutation and structural flexibilities in viral proteins quickly make them resistant to the host immune system and existing antiviral strategies. For most of the pathogenic viruses, the key survival strategies lie in their ability to evolve rapidly through mutations that affects the protein structure and function. Along with the experimental research related to antiviral development, computational data mining also plays an important role in deciphering the molecular and genomic signatures of the viral adaptability. Uncovering conserved regions in viral proteins with diverse chemical and biological properties is an important area of research for developing antiviral therapeutics, though assigning those regions is not a trivial work. Advancement in protein structural information databases and repositories, made by experimental research accelerated the in-silico mining of the data to generate more integrative information. Despite of the huge effort on correlating the protein structural information with its sequence, it is still a challenge to defeat the high mutability and adaptability of the viral genomics structure. In this current study, the authors have developed a user-friendly web application interface that will allow users to study and visualize protein segment variabilities in viral proteins and may help to find antiviral strategies. The present work of web application development allows thorough mining of the surface properties and variabilities of viral proteins which in combination with immunogenicity and evolutionary properties make the visualization robust. In combination with previous research on 20-Dimensional Euclidian Geometry based sequence variability characterization algorithm, four other parameters has been considered for this platform: [1] predicted solvent accessibility information, [2] B-Cell epitopic potential, [3] T-Cell epitopic potential and [4] coevolving region of the viral protein. Uniqueness of this study lies in the fact that a protein sequence stretch is being characterized rather than single residue-based information, which helps to compare properties of protein segments with variability. In current work, as an example, beside presenting the web application platform, five proteins of SARS-CoV2 was presented with keeping focus on protein-S. Current web-application database contains 29 proteins from 7 viruses including a GitHub repository of the raw data used in this study. The web application is up and running in the following address: http://www.protsegvar.com.

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Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel in Silico Method

10.26434/chemrxiv.12248561.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Milan Sencanski ◽

Vladimir Perovic ◽

Snezana Pajovic ◽

Miroslav Adzic ◽

Slobodan Paessler ◽

...

Keyword(s):

Protease Inhibitors ◽

In Silico ◽

Drug Target ◽

Transmission Rate ◽

Experimental Testing ◽

Drug Repurposing ◽

Global Public Health ◽

Main Protease ◽

Additional Approach ◽

Drugbank Database

The SARS-CoV-2 outbreak caused an unprecedented global public health threat, having a high transmission rate with currently no drugs or vaccines approved. An alternative powerful additional approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 main protease is essential for viral replication and an attractive drug target. In this study, we used the virtual screening (VS) protocol with both long-range and short-range interactions to select candidate SARS-CoV-2 main protease inhibitors. First, the ISM applied for Small Molecules was used for searching the Drugbank database and further followed by molecular docking. After in silico screening of drug space, we identified 57 drugs as potential SARS-CoV-2 main protease inhibitors that we propose for further experimental testing.

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