Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (M<sup>PRO</sup>) through <i>in silico</i> screening supported by molecular docking and a fragment-based pharmacophore model

Franco, Lucas S.; Maia, Rodolfo do Couto; Barreiro, Eliezer J.

doi:10.1039/d0md00282h

Cited by 16 publications

(17 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two residues with the highest interaction frequencies from this pocket were M49 (65%) and H164 (58%) which formed hydrophobic and weak hydrogen bond interactions, while M165 (47%) and Q189 (43%) interacted mainly by hydrophobic contacts with the ligands (Figure 3B and 4A). The high frequency of interactions with S1 and S2 residues showed that most of the ligands fill one or both pockets, conserving a more polar profile for S1, whereas the S2 retained a more aromatic and aliphatic profile as observed previously with the SARS-CoV Mpro [118] and in other studies with SARS-CoV-2 Mpro [119,120].…”

Section: Available Mpro Structures Show Conserved Conformation Protein-ligand Interactions and Location Of Waters Moleculessupporting

confidence: 77%

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Santos¹,

Kronenberger

Almeida

et al. 2022

Preprint

View full text Add to dashboard Cite

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In the present work, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 66 μM. In addition, eight compounds inhibited PLpro with IC50 ranging from 1.7 μM to 46 μM. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

show abstract

Section: Available Mpro Structures Show Conserved Conformation Protein-ligand Interactions and Location Of Waters Moleculessupporting

confidence: 77%

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Santos¹,

Kronenberger

Almeida

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This study yielded a significant number of novel chemotypes, suitable for future medicinal chemistry optimization, but also yielded one of the most potent Mpro inhibitors that emerged from only molecular docking 8,[52][53][54] .…”

Section: Discussionmentioning

confidence: 99%

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Here, His 41 forms hydrophobic interactions and His 163 donates hydrogen bonds whereas Glu 166 serves as a hydrogen bond donor or acceptor. A 3-amino-pyridinyl moiety found in several fragments including 1, TRY-UNI-714a760b-6, and EDG-MED-0da5ad92–2 was also found to show effective inhibitory properties with respective IC 50 values of 24.57 and 53.72 μM ( Franco et al, 2020 ). An amino acid decomposition analysis together with a molecular dynamic simulation was also applied when looking for SARS-CoV-2 M pro inhibitors where hydrogen bonds and hydrophobic interactions were found to hold the complex ( Choudhury, 2020 ).…”

Section: Potential Inhibitors Of Sars-cov-2 M Promentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

View full text Add to dashboard Cite

The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

show abstract

Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (M^PRO) through in silico screening supported by molecular docking and a fragment-based pharmacophore model

Abstract: A SARS-CoV-2 main protease (MPRO) inhibitor was discovered employing molecular docking and a fragment-based pharmacophore model as virtual screening strategies.

Cited by 16 publications

References 51 publications

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Contact Info

Product

Resources

About

Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (MPRO) through in silico screening supported by molecular docking and a fragment-based pharmacophore model

Abstract: A SARS-CoV-2 main protease (MPRO) inhibitor was discovered employing molecular docking and a fragment-based pharmacophore model as virtual screening strategies.

Cited by 16 publications

References 51 publications

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Contact Info

Product

Resources

About

Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (M^PRO) through in silico screening supported by molecular docking and a fragment-based pharmacophore model