A blueprint for high affinity SARS-CoV-2 Mpro inhibitors from activity-based compound library screening guided by analysis of protein dynamics

Goßen, Jonas; Albani, Simone; Hanke, Anton; Joseph, Benjamin P.; Bergh, Cathrine; Kuzikov, Maria; Costanzi, Elisa; Manelfi, Candida; Storici, Paola; Gribbon, Philip; Beccari, Andrea R.; Talarico, Carmine; Spyrakis, Francesca; Lindahl, Erik; Zaliani, Andrea; Carloni, Paolo; Wade, Rebecca C.; Musiani, Francesco; Kokh, Daria B.; Rossetti, Giulia

doi:10.1101/2020.12.14.422634

Cited by 2 publications

(1 citation statement)

References 120 publications

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“…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

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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.

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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

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A Pharmacophore Model for SARS-CoV-2 3CLpro Small Molecule Inhibitors and in Vitro Experimental Validation of Computationally Screened Inhibitors

Glaab

Manoharan

Abankwa

2021

Preprint

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Among the biomedical efforts in response to the current coronavirus (COVID-19) pandemic, pharmacological strategies to reduce viral load in patients with severe forms of the disease are being studied intensively. One of the main drug target proteins proposed so far is the SARS-CoV-2 viral protease 3CLpro (also called Mpro), an essential component for viral replication. Ongoing ligand- and receptor-based computational screening efforts would be facilitated by an improved understanding of the electrostatic, hydrophobic and steric features that characterize small molecule inhibitors binding stably to 3CLpro, as well as by an extended collection of known binders.Here, we present combined virtual screening, molecular dynamics simulation, machine learning and in vitro experimental validation analyses which have led to the identification of small molecule inhibitors of 3CLpro with micromolar activity, and to a pharmacophore model that describes functional chemical groups associated with the molecular recognition of ligands by the 3CLpro binding pocket. Experimentally validated inhibitors using a ligand activity assay include natural compounds with available prior knowledge on safety and bioavailability properties, such as the natural compound rottlerin (IC50 = 37 μM), and synthetic compounds previously not characterized (e.g. compound CID 46897844, IC50 = 31 μM). In combination with the developed pharmacophore model, these and other confirmed 3CLpro inhibitors may provide a basis for further similarity-based screening in independent compound databases and structural design optimization efforts, to identify 3CLpro ligands with improved potency and selectivity.Overall, this study suggests that the integration of virtual screening, molecular dynamics simulations and machine learning can facilitate 3CLpro-targeted small molecule screening investigations. Different receptor-, ligand- and machine learning-based screening strategies provided complementary information, helping to increase the number and diversity of identified active compounds. Finally, the resulting pharmacophore model and experimentally validated small molecule inhibitors for 3CLpro provide resources to support follow-up computational screening efforts for this drug target.

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A blueprint for high affinity SARS-CoV-2 Mpro inhibitors from activity-based compound library screening guided by analysis of protein dynamics

Cited by 2 publications

References 120 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

A Pharmacophore Model for SARS-CoV-2 3CLpro Small Molecule Inhibitors and in Vitro Experimental Validation of Computationally Screened Inhibitors

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