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Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.

ABSTRACT: We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.

SUBMITTER: Macchiagodena M

PROVIDER: S-EPMC8491126 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332.

Project description: Not available

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Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332.

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The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern.

Project description:There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.

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Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations.

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Structural basis of main proteases of HCoV-229E bound to inhibitor PF-07304814 and PF-07321332.

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Repurposing Halicin as a potent covalent inhibitor for the SARS-CoV-2 main protease.

Project description:The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (MPro), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with MPro. The in vitro potency test shows that halicin inhibits the activity of MPro an IC50 of 181.7 nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of MPro. Interaction and conformational changes inside the active site of MPro suggest a favorable nucleophilic aromatic substitution reaction mechanism between MPro C145 and halicin, explaining the high inhibition potency of halicin towards MPro.

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In Silico Characterization of Masitinib Interaction with SARS-CoV-2 Main Protease.

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SARS-CoV and SARS-CoV-2 main protease residue interaction networks change when bound to inhibitor N3.

Project description:COVID-19 is a respiratory disease caused by the coronavirus SARS-CoV-2. SARS-CoV-2 has many similarities with SARS-CoV. Both viruses rely on a protease called the main protease, or Mpro, for replication. Therefore, inhibiting Mpro may be a successful strategy for treating COVID-19. Structures of the main proteases of SARS-CoV and SARS-CoV-2 with and without inhibitor N3 are available in the Protein Data Bank. Comparing these structures revealed residue interaction network changes associated with N3 inhibition. Comparing network clustering with and without inhibitor N3 identified the formation of a cluster of residues 17, 18, 30-33, 70, 95, 98, 103, 117, 122, and 177 as a network change in both viral proteases when bound to inhibitor N3. Betweenness and stress centrality differences as well as differences in bond energies and relative B-factors when comparing free Mpro to inhibitor-bound Mpro identified residues 131, 175, 182, and 185 as possibly conformationally relevant when bound to the inhibitor N3. Taken together, these results provide insight into conformational changes of betacoronavirus Mpros when bound to an inhibitor.

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Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188.

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Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.

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