The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro)

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Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents

Lara Alzyoud et al.

Summary: This review paper provides a detailed insight into the potential of Mpro allosteric sites as drug targets for the treatment of COVID-19, as well as experimental and computational attempts to discover new allosteric inhibitors.

DRUG DESIGN DEVELOPMENT AND THERAPY (2022)

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Article Biochemistry & Molecular Biology

The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation

Radwa E. Mahgoub et al.

Summary: This study conducted structure-based virtual screening of a large ligand library to identify compounds with potential inhibition of the main protease enzyme of SARS-CoV-2. Three compounds showed promising inhibitory activity and had interesting drug-like characteristics, making them attractive candidates for future COVID-19 treatments.

MOLECULES (2022)

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Structural insights into SARS-CoV-2 proteins

Rimanshee Arya et al.

Summary: The unprecedented scale of the ongoing COVID-19 pandemic has led to an intensive global scientific effort to understand various aspects of the disease in a short period. More than three hundred experimental structures of SARS-CoV-2 proteins have been determined recently, revealing the intricate workings of the viral machinery and their potential as drug targets.

JOURNAL OF MOLECULAR BIOLOGY (2021)

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Article Multidisciplinary Sciences

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

Dafydd R. Owen et al.

Summary: PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor, has been discovered with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. This new drug has shown promise in countering the threat of COVID-19 with its oral activity and safety in clinical trials.

SCIENCE (2021)

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

Hylemariam Mihiretie Mengist et al.

Summary: The COVID-19 pandemic continues to devastate the world without approved antiviral drugs or vaccines, leading to rising cases and deaths. Current patient management relies on supportive care and repurposed drugs, while ongoing studies focus on potential inhibitors to the main protease of SARS-CoV-2.

FRONTIERS IN CHEMISTRY (2021)

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Article Cell Biology

Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CLpro substrate degradome

Isabel Pablos et al.

Summary: Research on the main viral protease of SARS-CoV-2 and its relationship with human protein substrates has revealed a large group of substrates, accelerating the exploration of pathophysiology and drug design. The study also demonstrates the interactions between 3CL(pro) and the Hippo pathway and other key effector proteins in human cells.

CELL REPORTS (2021)

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Article Chemistry, Medicinal

Elucidation of Cryptic and Allosteric Pockets within the SARS-CoV-2 Main Protease

Terra Sztain et al.

Summary: By using Gaussian accelerated molecular dynamics, this study identified cryptic pockets within the SARS-CoV-2 main protease, revealing druggable conformational states far from the active site. The simulations demonstrated comparable dynamics and pocket volumes to conventional brute force simulations conducted on significantly longer timescales.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2021)

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Article Multidisciplinary Sciences

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Sebastian Guenther et al.

Summary: The study identified 37 compounds that bind to the SARS-CoV-2 main protease through a high-throughput x-ray crystallographic screen of two repurposing drug libraries. Among these compounds, one peptidomimetic and six nonpeptidic compounds showed antiviral activity in cell-based viral reduction assays at nontoxic concentrations. The identification of two allosteric binding sites presents potential targets for drug development against SARS-CoV-2.

SCIENCE (2021)

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Article Multidisciplinary Sciences

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

Lucia Silvestrini et al.

Summary: The study investigated the structural features and thermodynamics of the SARS-CoV-2 M-pro protein using Small Angle X-ray Scattering (SAXS), providing key information for therapeutic intervention. It was found that small molecule inhibitors can affect dimerization and enzymatic activity of M-pro to varying extents, potentially serving as leads for antiviral drug development.

SCIENTIFIC REPORTS (2021)

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Article Pharmacology & Pharmacy

Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro

Ruikun Du et al.

Summary: The study found that chebulagic acid and punicalagin can inhibit the replication of SARS-CoV-2 virus in cells, and reduce virus-induced plaque formation at noncytotoxic concentrations, by regulating the enzymatic activity of viral protease as allosteric regulators.

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Oxindole and its derivatives: A review on recent progress in biological activities

Yogesh Mahadu Khetmalis et al.

Summary: Oxindole is a pharmacologically advantageous scaffold with various biological properties, commonly found in plant-based alkaloids, which can be modified to generate novel biological functions. It has been shown to have potential as a successful pharmaceutical agent with a wide range of activities beyond anticancer properties.

BIOMEDICINE & PHARMACOTHERAPY (2021)

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Article Biochemistry & Molecular Biology

Dimethyl sulfoxide reduces the stability but enhances catalytic activity of the main SARS-CoV-2 protease 3CLpro

Juliana C. Ferreira et al.

Summary: DMSO affects the activity of 3CLpro, with a 20% concentration improving the catalytic efficiency and peptide-binding affinity, while reducing aggregation.

FASEB JOURNAL (2021)

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Article Biochemistry & Molecular Biology

A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process

G. D. Noske et al.

Summary: This study characterized multiple forms of the SARS-CoV-2 main protease and identified the effects of extra N-terminal residues on its structure and activity, as well as a serine site-directed mutant as a transitional state during the C-terminal trans-cleavage. These findings shed light on the self-maturation process of the main protease and may guide therapeutic development.

JOURNAL OF MOLECULAR BIOLOGY (2021)

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Article Chemistry, Physical

Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface

Dina El Ahdab et al.

Summary: Through simulations, it was found that the hydrogen bond network at the dimerization interface of SARS-CoV-2 Main Protease is stable at physiological pH, with a buried allosteric site present. Differences in allosteric connectivity between PFFs and non-PFFs were observed, with water molecules at the interface playing a key role in mediating these interactions.

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A Novel Coronavirus from Patients with Pneumonia in China, 2019

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Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

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Interaction of the prototypical α-ketoamide inhibitor with the SARS-CoV-2 main protease active site in silico: Molecular dynamic simulations highlight the stability of the ligand-protein complex

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Room-temperature X-ray crystallography reveals the oxidation and reactivity of cysteine residues in SARS-CoV-2 3CL Mpro: insights into enzyme mechanism and drug design

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The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro)

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