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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Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure–Activity Relationship, and X-ray Structural Studies

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(19), P. 14702 - 14714

Published: Sept. 16, 2021

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited 3CLpro inhibitory IC50 value 250 nM an EC50 2.8 μM in VeroE6 cells. Remdesivir, RNA-dependent RNA polymerase inhibitor, showed 1.2 same assay. comparable activity with remdesivir immunocytochemistry assays. 7d N-allyl derivative most 73 nM. To obtain molecular insight into binding properties these molecules, crystal structures compounds 2, 7b, 9d-bound to SARS-CoV were determined, their compared.

Language: Английский

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Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 1306 - 1344

Published: Jan. 1, 2022

The emergence of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a long pandemic, with numerous cases and victims worldwide enormous consequences on social economic life. Although vaccinations have proceeded provide valuable shield against virus, approved drugs are limited it is crucial that further ways to combat infection developed, can also act potential mutations. main protease (Mpro) virus an appealing target for development inhibitors, due its importance viral life cycle high conservation among different coronaviruses. Several compounds shown inhibitory Mpro, both silico vitro, few them having entered clinical trials. These candidates include: known been repurposed, molecules specifically designed based natural substrate or structural moieties binding affinity active site, as well naturally derived compounds, either isolated plant extracts. aim this work collectively present results research regarding Mpro inhibitors date, focusing function founded by simulations explored vitro vivo assays. Creating extended portfolio promising may block replication inhibiting understanding involved structure-activity relationships, could basis effective solutions SARS-CoV-2 future related outbreaks.

Language: Английский

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Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(19), P. 13343 - 13364

Published: Sept. 15, 2022

The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. main protease (Mpro) is an promising target anti-SARS-CoV-2 drug design. Here, we report discovery potent non-covalent non-peptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. optimized compound GC-14 inhibits high potency (IC50 = 0.40 μM) displays excellent activity (EC50 1.1 μM), being than Remdesivir. Notably, exhibits low cytotoxicity (CC50 > 100 selectivity 50 μM cathepsins B, F, K, L, caspase 3). X-ray co-crystal structures prove that occupy multiple subpockets critical interactions. These studies may provide basis developing efficient safer therapy COVID-19.

Language: Английский

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Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS‐CoV‐2 Infection and COVID‐19

ChemMedChem, Journal Year: 2022, Volume and Issue: 17(22)

Published: Sept. 27, 2022

COVID-19, caused by SARS-CoV-2 infection, continues to be a major public health crisis around the globe. Development of vaccines and first cluster antiviral drugs has brought promise hope for prevention treatment severe coronavirus disease. However, continued development newer, safer, more effective are critically important combat COVID-19 counter looming pathogenic variants. Studies life cycle revealed several biochemical targets drug development. In present review, we focus on recent design medicinal chemistry efforts in small molecule discovery, including nirmatrelvir that viral protein synthesis remdesivir molnupiravir target RdRp. These FDA approved COVID-19.

Language: Английский

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Experimental Models of COVID-19

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 5, 2022

COVID-19 is the most consequential pandemic of 21 st century. Since earliest stage 2019-2020 epidemic, animal models have been useful in understanding etiopathogenesis SARS-CoV-2 infection and rapid development vaccines/drugs to prevent, treat or eradicate infection. Early SARS-CoV-1 research using immortalized in-vitro cell lines aided different cells receptors needed for and, due their ability be easily manipulated, continue broaden our disease in-vivo models. The scientific community determined as which could demonstrate viral infection, replication, transmission, spectrum illness seen human populations. Until now, there not well-described although transgenic mouse (i.e. mice with humanized ACE2 receptors) proposed. Additionally, are only limited facilities (Biosafety level 3 laboratories) available contribute aid eventually exterminating around world. This review summarizes successful including studies Non-Human Primates (NHPs) were found susceptible transmitted virus similarly humans (e.g., Rhesus macaques, Cynomolgus, African Green Monkeys), that do require Biosafety laboratories Mouse Hepatitis Virus COVID-19, Ferret model, Syrian Hamster model). Balancing safety, mimicking robustness Murine Virus-1 model currently represents optimal SARS-CoV-2/COVID19 research. Exploring future will researchers/scientists discovering mechanisms identifying therapies prevent COVID-19.

Language: Английский

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Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

Biomolecules, Journal Year: 2023, Volume and Issue: 13(9), P. 1339 - 1339

Published: Sept. 2, 2023

The main protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered highly conserved viral target. Disruption catalytic activity Mpro produces detrimental effect on course infection, making this target one most attractive for treatment COVID-19. current success SARS-CoV-2 inhibitor Nirmatrelvir, first oral drug forms COVID-19, has further focused attention researchers important target, search new inhibitors thriving exciting field development antiviral drugs active against related coronaviruses.

Language: Английский

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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Future Pharmacology, Journal Year: 2023, Volume and Issue: 3(1), P. 80 - 107

Published: Jan. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Language: Английский

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

Protein Science, Journal Year: 2023, Volume and Issue: 32(8)

Published: June 25, 2023

Abstract Antiviral therapeutics to treat SARS‐CoV‐2 are needed diminish the morbidity of ongoing COVID‐19 pandemic. A well‐precedented drug target is main viral protease (M Pro ), which targeted by an approved and several investigational drugs. Emerging resistance has made new inhibitor chemotypes more pressing. Adopting a structure‐based approach, we docked 1.2 billion non‐covalent lead‐like molecules library 6.5 million electrophiles against enzyme structure. From these, 29 11 covalent inhibitors were identified in 37 series, most potent having IC 50 20 μM, respectively. Several series optimized, resulting low micromolar inhibitors. Subsequent crystallography confirmed docking predicted binding modes may template further optimization. While aid optimization M for SARS‐CoV‐2, modest success rate also reveals weaknesses our approach challenging targets like versus other where it been successful, techniques itself.

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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