Structural insights of key enzymes into therapeutic intervention against SARS-CoV-2

Shahid, Munazza; Shahzad‐ul‐Hussan, Syed

doi:10.1016/j.jsb.2020.107690

Cited by 10 publications

(14 citation statements)

References 94 publications

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“…Proline-type derivatives (1-3) moderately inhibited M pro , but their inhibitory activities were obviously weaker than those of the malonic acid-type derivatives. Fullerenol (5) showed no inhibitory activity against M pro at 1.0 mM, indicating that a number of hydroxy groups attached to the fullerene surface lost the inhibitory activity. Compound 4, which has a hydroxymethylcarbonyl moiety, is a transition-state mimic isostere of HIV protease substrate processing and showed potent e cacy against HIV protease in our previous report, [12] and it exhibited weak inhibition against M pro .…”

Section: Resultsmentioning

confidence: 99%

“…Among the 16 nonstructural proteins, nsp3 (papain-like protease, PL pro ), nsp5 (main protease, M pro , or 3-chymotrypsin-like protease, 3CL pro ), nsp12 (RNA-dependent RNA polymerase), nsp13 (helicase), nsp14 (N7-methyltransferase), and nsp16 (2'-O-methyltransferase) act as enzymes. [5] Thus, while there are many potential targets for COVID-19, SARS-CoV-2 M pro plays an important role in the cleavage of viral polyproteins into functional proteins and is recognized as an attractive target for antiviral drugs. SARS-CoV-2 M pro is a cysteine protease with a catalytic dyad comprised of Cys145 and His41.…”

Section: Introductionmentioning

confidence: 99%

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Malonic Acid-Type Fullerene Derivatives Strongly Inhibit The SARS-Cov-2 Main Protease

Katagishi

Yasuda

Takahashi

et al. 2022

Preprint

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Malonic Acid-Type Fullerene Derivatives Strongly Inhibit The SARS-Cov-2 Main Protease

Katagishi

Yasuda

Takahashi

et al. 2022

Preprint

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“…Four key enzymes of SARS-COV-2, such as RdRp, 3CLp, papain-like protease, helicase, and ACE-2; and transmembrane serine protease (Host factors), play an essential role in disease establishment. Interestingly, α-glucosidase in the endoplasmic reticulum is a promising target for exploring anti-SARS-CoV-2 medicines 23 .…”

Section: Coronavirus Classification and Mechanism Of Cell Entrymentioning

confidence: 99%

An Overview of COVID-19 and the Potential Plant Harboured Secondary Metabolites against SARS-CoV-2: A Review

Swamy¹

2021

J. Pure Appl. Microbiol.

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The SARS-CoV-2 virus causes COVID-19, a pandemic disease, and it is called the novel coronavirus. It belongs to the Coronaviridae family and has been plagued the world since the end of 2019. Viral infection to the lungs causes fluid filling and breathing difficulties, which leads to pneumonia. Pneumonia progresses to ARDS (Acute Respiratory Distress Syndrome), in which fluid fills the air sac and seeps from the pulmonary veins. In the current scenario, several vaccines have been used to control the pandemic worldwide. Even though vaccines are available and their effectiveness is short, it may be helpful to curb the pandemic, but long-term protection is inevitable when we look for other options. Plants have diversified components such as primary and secondary metabolites. These molecules show several activities such as anti-microbial, anti-cancer, anti-helminthic. In addition, these molecules have good binding ability to the SARS-CoV-2 virus proteins such as RdRp (RNA-dependent RNA polymerase), Mpro (Main Protease), etc. Therefore, these herbal molecules could probably be used to control the COVID-19. However, pre-requisite tests, such as cytotoxicity, in vivo, and human experimental studies, are required before plant molecules can be used as potent drugs. Plant metabolites such as alkaloids, isoquinoline ß-carboline, and quinoline alkaloids such as skimmianine, quinine, cinchonine, and dictamine are present in plants and used in a traditional medicinal system.

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“…The 3-Chymotrypsin-like protease (3CL pro ) is a cysteine protease that facilitates the proteolytic processing of the viral polyproteins to yield functional proteins essential for the packaging of new virions [ 6 ]. It is one of the most important components of viral replication as it cleaves the replicase polyprotein after its translation at 11 different sites releasing most of the functional protein components of the replicase-transcriptase complex, hence it is also known as main protease (M pro ) of coronaviruses [ 7 ]. Amino acid sequence alignments of this protease revealed that, SARS-CoV-2 3CL pro had ∼96% sequence identity with the previous SARS-CoV 3CL pro , and ∼50% sequence identity with MERS-CoV 3CL pro [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Its substrate specificity is primarily defined by the residues at the P1, P1′ and P2 positions of the peptide substrate. These positions are highly conserved in all coronaviruses in particular the presence of glutamine at the P1 position (N-terminus of the scissile bond) of the substrate is strictly required for 3CL pro binding across all coronaviruses [ 7 ]. Inhibition of 3CL pro by compounds is not expected to interfere with human proteases since the protease has no homologue in human [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

Gyebi

Elfiky

Ogunyemi

et al. 2021

Computers in Biology and Medicine

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An in-house library of 173 phytocompound structures from Vernonia amygdalina and Occinum gratissimum was screened against the active region of 3-Chymotrypsin-Like Protease (3CL pro ) of SARS-CoV-2 in silico. Based on docking scores and reference inhibitors, a hit-list of 21 phytocompounds, with binding energies ranging from − 7.2 to -8.0 kcal/mol, was initially generated. Further docking against the 3CL pro of related coronaviruses (SARS-CoV and MERS-CoV), docking to 5 different representative conformations generated from the cluster analysis of SARS-CoV-2 3CL pro molecular dynamics simulation (MDS) trajectories, and in silico drug-likeness analyses, revealed two drug-like terpenoid structures as promising non-covalent inhibitors of SARS-CoV-2 3CL Pro viz: neoandrographolide and vernolide. These terpenoid structures are accommodated within the substrate-binding pocket, and interacted with the catalytic dyad, the oxyanion loop (residues 138-145), and the S1/S2 subsites of the enzyme active site. With the aid of an array of hydrogen bonds and hydrophobic interactions with residues 142-145, these phytocompounds may stabilize the conformation of the exible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during proteolytic cleavage. Molecular dynamics simulation and binding free energy calculation further revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability, which could be adapted for experimental models.

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Structural insights of key enzymes into therapeutic intervention against SARS-CoV-2

Abstract: Graphical abstract

Cited by 10 publications

References 94 publications

Malonic Acid-Type Fullerene Derivatives Strongly Inhibit The SARS-Cov-2 Main Protease

Malonic Acid-Type Fullerene Derivatives Strongly Inhibit The SARS-Cov-2 Main Protease

An Overview of COVID-19 and the Potential Plant Harboured Secondary Metabolites against SARS-CoV-2: A Review

Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

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