Mechanistic Insights into Targeting SARS-CoV-2 Papain-like Protease in the Evolution and Management of COVID-19

BioChem, Journal Year: 2024, Volume and Issue: 4(3), P. 268 - 299

Published: Sept. 23, 2024

The COVID-19 pandemic, instigated by the emergence of novel coronavirus, SARS-CoV-2, created an incomparable global health crisis. Due to its highly virulent nature, identifying potential therapeutic agents against this lethal virus is crucial. PLpro a key protein involved in viral polyprotein processing and immune system evasion, making it prime target for development antiviral drugs combat COVID-19. To expedite search candidates, review delved into computational studies. Recent investigations have harnessed methods identify promising inhibitors targeting PLpro, aiming suppress activity. Molecular docking techniques were employed researchers explore binding sites within catalytic region PLpro. elucidates functional structural properties SARS-CoV-2 underscoring significance pathogenicity replication. Through comprehensive all-atom molecular dynamics (MD) simulations, stability drug–PLpro complexes was assessed, providing dynamic insights their interactions. By evaluating energy estimates from MD stable with identified. This offers overview drug/lead candidates discovered thus far using diverse silico methodologies, encompassing drug repurposing, structure-based, ligand-based virtual screenings. Additionally, identified are listed based on chemical structures meticulously examined according various parameters, such as estimated free (ΔG), types intermolecular interactions, PLpro–ligand complexes, determined outcomes simulations. Underscoring pivotal role battle COVID-19, establishes robust foundation integrating modeling, insights. continual imperative improvement existing exploring compounds remains paramount efforts evolution management hinge symbiotic relationship between experimental validation, interdisciplinary synergy crucial endeavor.

Language: Английский

---

Systematic identification of chemical components in Fufang Shuanghua oral liquid and screening of potential active components against SARS-CoV-2 protease

Journal of Pharmaceutical and Biomedical Analysis, Journal Year: 2022, Volume and Issue: 223, P. 115118 - 115118

Published: Oct. 21, 2022

Language: Английский

---

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 8

Published: Jan. 24, 2022

The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, eleven conserved sites, which leads to formation mature nonstructural proteins essential replication virus. Due its role, numerous studies have been conducted so far, confirmed 3CLpro an attractive drug target combat Covid-19 reported vast number inhibitors their co-crystal structures. Despite all ongoing efforts, D-peptides, possess key advantages over L-peptides therapeutic agents, not explored potential candidates against 3CLpro. current work fills this gap by reporting in silico approach discovery D-peptides capable inhibiting that involves structure-based virtual screening (SBVS) in-house library D-tripeptides D-tetrapeptides into active site subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations molecular dynamics (MD) simulations. In vitro enzymatic assays four top-scoring 20 μM showed them caused 55-85% inhibition activity, thus highlighting suitability devised approach. Overall, our results present promising computational strategy identify 3CLpro, with broader application problems involving protein inhibition.

Language: Английский

---

Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 38(1), P. 24 - 35

Published: Oct. 28, 2022

Ligand-based drug design methods are thought to require large experimental datasets become useful for virtual screening. In this work, we propose a computational strategy novel inhibitors of coronavirus main protease, Mpro. The pipeline integrates publicly available screening and binding affinity data in two-stage machine-learning model using the recent MACAW embeddings. Once trained, can be deployed rapidly screen libraries molecules silico. Several hundred thousand compounds were virtually screened 10 them selected testing. From these compounds, 8 showed clear inhibitory effect on recombinant Mpro, with half-maximal concentration values (IC50) range 0.18-18.82 μM. Cellular assays also conducted evaluate cytotoxic, haemolytic, antiviral properties. A promising lead compound against Mpro was identified dose-dependent inhibition virus infectivity minimal toxicity human MRC-5 cells.

Language: Английский

---

What do we know about the function of SARS-CoV-2 proteins?

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 18, 2023

The COVID-19 pandemic has highlighted the importance in understanding of biology SARS-CoV-2. After more than two years since first report COVID-19, it remains crucial to continue studying how SARS-CoV-2 proteins interact with host metabolism cause COVID-19. In this review, we summarize findings regarding functions 16 non-structural, 6 accessory and 4 structural proteins. We place less emphasis on spike protein, which been subject several recent reviews. Furthermore, comprehensive reviews about therapeutic have also published. Therefore, do not delve into details these topics; instead direct readers those other To avoid confusions what know from coronaviruses, exclusively that experimentally confirmed identified mechanisms appear be primary targets proteins, including gene expression immune response pathways such as ribosome translation, JAK/STAT, RIG-1/MDA5 NF-kβ pathways. Additionally, emphasize multiple exhibited by along limited information available for some Our aim review is assist researchers contribute ongoing comprehension SARS-CoV-2’s pathogenesis.

Language: Английский

---