Screening for Inhibitors of Main Protease in SARS-CoV-2: In Silico and In Vitro Approach Avoiding Peptidyl Secondary Amides

Objective:: Recent pandemic caused by SARS-CoV-2 described in Wuhan China in December-2019 spread widely almost all the countries of the world. Corona virus (COVID-19) is causing the unexpected death of many peoples and severe economic loss in several countries. Virtual screening based on molecular docking, drug-likeness prediction, and in silico ADMET study has become an effective tool for the identification of small molecules as novel antiviral drugs to treat diseases. Methods:: In the current study, virtual screening was performed through molecular docking for identifying potent inhibitors against Mpro enzyme from the ZINC library for the possible treatment of COVID-19 pandemic. Interestingly, some compounds are identified as possible anti-covid-19 agents for future research. 350 compounds were screened based on their similarity score with reference compound X77 from ZINC data bank and were subjected to docking with crystal structure available of Mpro enzyme. These compounds were then filtered by their in silico ADME-Tox and drug-likeness prediction values. Result:: Out of these 350 screened compounds, 10 compounds were selected based on their docking score and best docked pose in comparison to the reference compound X77. In silico ADME-Tox and drug likeliness predictions of the top compounds were performed and found to be excellent results. All the 10 screened compounds showed significant binding pose with the target enzyme main protease (Mpro) enzyme and satisfactory pharmacokinetic and toxicological properties. Conclusion:: Based on results we can suggest that the identified compounds may be considered for therapeutic development against the COVID-19 virus and can be further evaluated for in vitro activity, preclinical, clinical studies and formulated in a suitable dosage form to maximize their bioavailability.

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In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210317162502 ◽

2021 ◽

Vol 18 ◽

Author(s):

Jainey James ◽

Divya Jyothi ◽

Sneh Priya

Keyword(s):

Antiviral Activity ◽

Molecular Interactions ◽

In Silico ◽

Antiviral Treatment ◽

In Vivo Studies ◽

Main Protease ◽

Hypothesis Model ◽

Antiviral Activities ◽

Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

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FBDD: In-silico STRATEGY TO INHIBIT MPRO ACTIVITY USING DRUGS FROM PREVIOUS OUTBREAKS

Journal of Experimental Biology and Agricultural Sciences ◽

10.18006/2021.9(4).472.480 ◽

2021 ◽

Vol 9 (4) ◽

pp. 472-480

Author(s):

Gauravi N Trivedi ◽

◽

Janhavi T Karlekar ◽

Khushbu Dhimmar ◽

Hetal kumar Panchal ◽

...

Keyword(s):

Drug Development ◽

In Silico ◽

Drug Targets ◽

Transmission Rate ◽

Respiratory Illness ◽

Primary Treatment ◽

Rational Drug Design ◽

New Drugs ◽

Main Protease

Main protease (Mpro) and Spike (S) proteins are said potential drug targets of COVID-19. Pneumonia like respiratory illness caused by SARS-CoV-2 is spreading rapidly due to its replication and transmission rate. Protease is the protein that is involved in both replication and transcription. Since CoV-2 shares, genomic similarity with CoV and MERS-CoV, drugs from previous outbreaks are used as primary treatment of the disease. In-silico drug development strategies are said to be faster and effective than in-vitro with a lesser amount of risk factors. Fragment Based Drug Designing (FBDD), also known as rational drug design in which a potential target protein is selected and docked with a lead-like molecule that eventually leads to drug development. Nine (9) drugs that are currently being used to treat patients of coronavirus were selected in this study from the latest literature review and fragmented as per rules followed by crosslinking of drug fragments using editor tools. These native drugs and synthesized drugs were then docked against the main protease. Results of the study revealed that one of the crosslinked lead-like compounds showed a higher binding affinity (∆G) more than any of the native compounds. Further, the results of this study suggested that the combination of potential drugs can be an effective way to develop new drugs to treat a deadly disease.

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In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

10.26434/chemrxiv.12598487 ◽

2020 ◽

Author(s):

Tamara Rubilar ◽

Elena Susana Barbieri ◽

Ayelén Gázquez ◽

Marisa Avaro ◽

Mercedes Vera-Piombo ◽

...

Keyword(s):

Sea Urchin ◽

In Silico ◽

De Novo ◽

Drug Repurposing ◽

In Silico Analysis ◽

Promising Alternative ◽

In Silico Docking ◽

Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2.

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In silico SCREENING OF Ziziphus spina-christi (L.) Desf. AND Strychnos ligustrine COMPOUNDS AS A PROTEASE INHIBITOR OF SARS-COV-2

Journal of Experimental Biology and Agricultural Sciences ◽

10.18006/2021.9(spl-2-icopmes_2020).s208.s214 ◽

2021 ◽

Vol 9 (Spl-2-ICOPMES_2020) ◽

pp. S208-S214

Author(s):

Novi Yantih ◽

◽

Uthami Syabillawati ◽

Esti Mulatsari ◽

Wahono Sumaryono ◽

...

Keyword(s):

In Silico ◽

Data Bank ◽

Binding Pocket ◽

In Vivo Studies ◽

In Silico Screening ◽

Main Protease ◽

Docking Method ◽

Inhibitory Site

Diseases caused by the coronavirus have become an important concern in early 2020. The coronavirus is a new type of virus that is included in the SARS-CoV-2 group. One of the possible mechanisms of SARS-CoV-2 inhibition involves protease receptors inhibition. This research was aimed to in silico screening of Ziziphus spina-christi (L.) Desf., and Strychnos ligustrine active ingredients as the main protease inhibitors of SARS-CoV-2 by assessing the ligand-binding affinity in the binding pocket of SARS-CoV-2 main protease protein. The molecular docking method is generally used to predict the inhibitory site and bonds formation. In the current study, some generally used antiviral compounds from the PDB (Protein Data Bank) were also used to compare the affinity strength of the test compound against the protease receptor (code of 5R7Y). The inhibitory activity against the main protease receptor proven by the ChemPLP score is more negative than the receptor’s native ligand and the comparison compounds. Jubanine B, a compound of Z. spina-christi has the most robust inhibition activity on the SARS-CoV-2 protease receptor. Results of this study can be concluded that this can be used to develop as a candidate for traditional medicine against SARS-CoV-2 but still it required some more in vitro and in vivo studies.

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In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

10.26434/chemrxiv.12598487.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Tamara Rubilar ◽

Elena Susana Barbieri ◽

Ayelén Gázquez ◽

Marisa Avaro ◽

Mercedes Vera-Piombo ◽

...

Keyword(s):

Sea Urchin ◽

In Silico ◽

De Novo ◽

Drug Repurposing ◽

In Silico Analysis ◽

Promising Alternative ◽

In Silico Docking ◽

Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2.

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In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS‐CoV ‐2 main protease ( 3CLpro )

Phytotherapy Research ◽

10.1002/ptr.6998 ◽

2021 ◽

Author(s):

Abbas Khan ◽

Wang Heng ◽

Yanjing Wang ◽

Jingfei Qiu ◽

Xiaoyong Wei ◽

...

Keyword(s):

In Silico ◽

In Vitro Evaluation ◽

Potential Inhibitor ◽

Main Protease

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In silico Screening of Food Bioactive Compounds to Predict Potential Inhibitors of COVID-19 Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)

10.26434/chemrxiv.12051927.v2 ◽

2020 ◽

Cited By ~ 4

Author(s):

Brahmaiah Pendyala ◽

Ankit Patras

Keyword(s):

Rna Polymerase ◽

Bioactive Compounds ◽

In Silico ◽

World Health ◽

Rna Dependent Rna Polymerase ◽

In Silico Screening ◽

Main Protease ◽

Health Organization

As novel corona virus (COVID-19) infections has spread throughout the world, world health organization (WHO) has announced COVID-19 as a pandemic infection. Henceforth investigators are conducting extensive research to find possible therapeutic agents against COVID-19. Main protease (Mpro) that plays an essential role in processing the polyproteins that are translated from the 2019-nCOV RNA and RNA-dependent RNA polymerase (RdRp) that catalyzes the replication of RNA from RNA template becomes as a potential targets for in silico screening of effective therapeutic compounds to COVID-19. In this study we used COVID-19 Docking Server to predict potential food bioactive compounds to inhibit Mpro and RdRp. The results showed that Phycocyanobilin, Riboflavin, Cyanidin, Daidzein, Genistein are potent inhibitor bioactive compounds to Mpro and RdRp in comparison to antiviral drugs. Though, further in vitro and/or in vivo research is required to validate the docking results.

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