Mechanism of Inhibition of SARS-CoV-2 Mpro by N3 Peptidyl Michael Acceptor Explained by QM/MM Simulations and Design of New Derivatives with Tunable Chemical Reactivity

The SARS-CoV-2 main protease (Mpro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 Mpro with a known Michael acceptor (peptidyl) inhibitor, N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 Mpro, we design two new, synthetically accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of Mpro by these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor.

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Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity

Chemical Science ◽

10.1039/d0sc06195f ◽

2021 ◽

Author(s):

Kemel Arafet ◽

Natalia Serrano-Aparicio ◽

Alessio Lodola ◽

Adrian J. Mulholland ◽

Florenci V. González ◽

...

Keyword(s):

Chemical Reactivity ◽

Covalent Inhibition ◽

Mechanism Of Inhibition ◽

Main Protease ◽

Mechanism Of Reaction ◽

Michael Acceptor

QM/MM simulations identify the mechanism of reaction of N3, a covalent peptidyl inhibitor of SARS-CoV-2 main protease. Modelling of two novel proposed compounds, B1 and B2, suggests that reversibility of covalent inhibition could be tailored.

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Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Nature Communications ◽

10.1038/s41467-021-23313-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kangsa Amporndanai ◽

Xiaoli Meng ◽

Weijuan Shang ◽

Zhenmig Jin ◽

Michael Rogers ◽

...

Keyword(s):

Mass Spectrometry ◽

Chemical Reactivity ◽

Inhibition Mechanism ◽

Selenium Atom ◽

Binding Modes ◽

Mechanism Of Inhibition ◽

Main Protease ◽

Therapeutic Development ◽

Infected Cells ◽

Corona Viruses

AbstractThe SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.

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The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Scientific Reports ◽

10.1038/s41598-021-88630-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lucia Silvestrini ◽

Norhan Belhaj ◽

Lucia Comez ◽

Yuri Gerelli ◽

Antonino Lauria ◽

...

Keyword(s):

Enzymatic Activity ◽

Dissociation Constant ◽

Molecular Mechanisms ◽

Antiviral Drug ◽

Structural Features ◽

Experimental Information ◽

Detailed Knowledge ◽

Main Protease ◽

Equilibrium Dissociation ◽

Drug Leads

AbstractThe maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

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In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

Biochemistry and Biophysics Reports ◽

10.1016/j.bbrep.2021.100969 ◽

2021 ◽

pp. 100969

Author(s):

Azza H. Harisna ◽

Rizky Nurdiansyah ◽

Putri H. Syaifie ◽

Dwi W. Nugroho ◽

Kurniawan E. Saputro ◽

...

Keyword(s):

In Silico ◽

Spike Protein ◽

Main Protease ◽

Potential Inhibitors

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An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease

Molecular Informatics ◽

10.1002/minf.202000187 ◽

2021 ◽

Author(s):

Nemanja Djokovic ◽

Dusan Ruzic ◽

Teodora Djikic ◽

Sandra Cvijic ◽

Jelisaveta Ignjatovic ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Main Protease ◽

Potential Inhibitors

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Novel 1,2,3‐Triazole Derivatives as Potential Inhibitors against Covid‐19 Main Protease: Synthesis, Characterization, Molecular Docking and DFT Studies

ChemistrySelect ◽

10.1002/slct.202100522 ◽

2021 ◽

Vol 6 (14) ◽

pp. 3468-3486

Author(s):

Mohamed Reda Aouad ◽

Daoud J. O. Khan ◽

Musa A. Said ◽

Nadia S. Al‐Kaff ◽

Nadjet Rezki ◽

...

Keyword(s):

Molecular Docking ◽

Dft Studies ◽

Triazole Derivatives ◽

Main Protease ◽

Potential Inhibitors

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Quinoline and Quinazoline Alkaloids against COVID-19: An In Silico Multitarget Approach

Journal of Chemistry ◽

10.1155/2021/3613268 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Esraa M. O. A. Ismail ◽

Shaza W. Shantier ◽

Mona S. Mohammed ◽

Hassan H. Musa ◽

Wadah Osman ◽

...

Keyword(s):

Antimalarial Activity ◽

The Novel ◽

Socioeconomic Impacts ◽

Health Crisis ◽

Natural Sources ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Potential Inhibitors

The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

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In Silico Identification of Potential Inhibitors of the Main Protease of SERS-CoV-2 Using Combined Ligand-based and Structure-based Drug Design approach

Eurasian Journal of Medicine and Oncology ◽

10.14744/ejmo.2020.91768 ◽

2020 ◽

Author(s):

Sudhan Debnath

Keyword(s):

Drug Design ◽

In Silico ◽

Design Approach ◽

Structure Based Drug Design ◽

Main Protease ◽

In Silico Identification ◽

Potential Inhibitors

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Phenylbenzopyrone of flavonoids as a potential scaffold to prevent SARS-CoV-2 replication by inhibiting its MPRO main protease

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210127113027 ◽

2021 ◽

Vol 22 ◽

Author(s):

Angamba Meetei Potshangbam ◽

Potshangbam Nongdam ◽

A. Kiran Kumar ◽

R.S. Rathore

Keyword(s):

Antiviral Drugs ◽

Dynamics Simulation ◽

Compound Libraries ◽

Main Protease ◽

Enterovirus A71 ◽

Short Period ◽

Novel Coronavirus ◽

Effective Drugs ◽

Drug Leads ◽

Better Than

Background: In December 2019, an outbreak of a pneumonia-like illness, Coronavirusdisease-2019 (COVID-19), originating from Wuhan, China was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (MPRO) remains the most validated pharmacological target for the design and discovery of inhibitors. Objective: The purpose of the study was to find a prospective natural scaffold as an inhibitor for MPRO main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelflinavir. Methods: Natural compound libraries were screened for potential scaffold against MPRO main protease. Molecular dynamics simulation, MM-GBSA and principle component analyses of enzyme-ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir. Results: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with O-glycosidic form performing better than corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid as more suitable inhibitor with compounds rutin, procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin emerging as one of the best candidate compound. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) as well as implicated in lung fibrosis. Conclusion: The present study displaying flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.

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