Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115503 - 115503

Published: May 18, 2023

Language: Английский

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Identifying Inhibitor-SARS-CoV2-3CLpro Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations

Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 805 - 805

Published: Feb. 10, 2025

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in virus's life cycle and plays a pivotal role COVID-19. Understanding how small molecules inhibit 3CLpro's activity vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance sampling 3CLpro conformations conducted correlation network analysis (CNA) explore interactions between different structural domains. Our findings indicate that CNA-identified node domain II acts conduit, transferring conformational changes from catalytic regions domains I II, triggered by binding inhibitors (7YY, 7XB, Y6G), III, thereby modulating activity. Normal mode (NMA) principal component (PCA) revealed inhibitor affects flexibility collective movements sites influencing function. free energies, predicted both MM-GBSA QM/MM-GBSA methods, showed high with experimental data, validating reliability our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, E166, identified through residue-based energy decomposition, present promising targets design drugs could facilitate development clinically effective inhibitors.

Language: Английский

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Evolution of chemistry and selection technology for DNA-encoded library

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(2), P. 492 - 516

Published: Oct. 11, 2023

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and non-self-replicating phenotypes, generating a diverse world. In analogy with biological world, DEL world can evolve by using central dogma, wherein DNA replicates PCR reactions to amplify genetic codes, sequencing transcripts information, DNA-compatible synthesis translates into phenotypes. Importantly, is key expanding space. Besides, evolution-driven selection system pushes chemicals under selective pressure, i.e., desired strategies. this perspective, we summarized recent advances in synthetic toolbox panning strategies, which will shed light on drug discovery harnessing vitro evolution via DEL.

Language: Английский

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Structural biology of SARS-CoV-2 Mpro and drug discovery

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 82, P. 102667 - 102667

Published: Aug. 4, 2023

Language: Английский

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Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: April 9, 2024

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, 3C-like protease (3CLpro) that confer to novel non-covalent inhibitor, WU-04, which is currently phase III clinical trials (NCT06197217). Crystallographic analysis indicates M49K mutation destabilizes WU-04-binding pocket, impacting binding WU-04 more significantly than 3CLpro substrates. The M165V directly interferes with binding. S301P mutation, far from indirectly affects by restricting rotation 3CLpro's C-terminal tail impeding dimerization. We further explored mutations clinically used inhibitors: ensitrelvir nirmatrelvir, revealed trade-off between catalytic activity, thermostability, drug 3CLpro. found at same residue (M49) can have distinct effects on inhibitors, highlighting importance developing multiple antiviral agents different skeletons for fighting These findings enhance our understanding SARS-CoV-2 mechanisms inform therapeutics.

Language: Английский

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Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 797 - 797

Published: July 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Language: Английский

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Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds deaths each week. Due limited efficacy vaccines against resistance current therapies, additional anti-viral therapeutics with pan-coronavirus activity are high interest. Here, we screen 2.8 billion compounds from a DNA-encoded chemical library identify small molecules that non-covalent inhibitors targeting conserved 3CL protease other coronaviruses. We perform structure-based optimization, leading creation series potent, inhibitors, for coronavirus infections. To characterize their binding mechanism protease, determine 16 co-crystal structures find optimized specifically interact both protomers native homodimer protease. Since is catalytically competent only in dimeric state, these data provide insight into design drug-like state. With mode different covalent inhibitor nirmatrelvir, COVID drug Paxlovid, may overcome reported nirmatrelvir complement its clinical utility. therapies authors screened identified

Language: Английский

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The Chiral 5,6-Cyclohexane-fused Uracil Ring-System: a Molecular Platform with Promising Activity against SARS-CoV-2

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117302 - 117302

Published: Jan. 21, 2025

Language: Английский

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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(1), P. 87 - 109

Published: Aug. 9, 2023

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role the virus life cycle. covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) non-covalent ensitrelvir have shown efficacy clinical trials been approved therapeutic use. Effective antiviral drugs are needed to fight pandemic, while inhibitors could be promising alternatives due their selectivity favorable druggability. Numerous desirable properties developed based on available crystal structures Mpro. In this article, we describe medicinal chemistry strategies applied discovery optimization inhibitors, followed by general overview critical analysis information. Prospective viewpoints insights into current development also discussed.

Language: Английский

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On the origins of SARS-CoV-2 main protease inhibitors

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(1), P. 81 - 118

Published: Oct. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Language: Английский

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