Abstract
Using a combination of enhanced sampling molecular dynamics techniques and non-equilibrium alchemical transformations with full atomistic details, we have shown that hydroxychloroquine (HCQ) may act as a mild inhibitor of important functional proteins for SARS-CoV2 replication, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.
MeSH terms
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Betacoronavirus / isolation & purification
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Betacoronavirus / metabolism
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Binding Sites
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COVID-19
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Catalytic Domain
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Coronavirus 3C Proteases
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Coronavirus Infections / drug therapy
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Coronavirus Infections / pathology
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Coronavirus Papain-Like Proteases
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Humans
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Hydroxychloroquine / chemistry
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Hydroxychloroquine / metabolism*
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Hydroxychloroquine / therapeutic use
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Molecular Dynamics Simulation*
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Pandemics
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Papain / chemistry
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Papain / metabolism*
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Pneumonia, Viral / drug therapy
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Pneumonia, Viral / pathology
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RNA-Dependent RNA Polymerase / chemistry
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RNA-Dependent RNA Polymerase / metabolism*
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SARS-CoV-2
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Viral Nonstructural Proteins / chemistry
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Viral Nonstructural Proteins / metabolism*
Substances
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Viral Nonstructural Proteins
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Hydroxychloroquine
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RNA-Dependent RNA Polymerase
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Cysteine Endopeptidases
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Coronavirus Papain-Like Proteases
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Papain
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Coronavirus 3C Proteases