Identification of Natural Products Inhibiting SARS-CoV-2 by Targeting Viral Proteases: A Combined in Silico and in Vitro Approach DOI Creative Commons
Andreas Wasilewicz, Benjamin Kirchweger, Denisa Bojková

et al.

Journal of Natural Products, Journal Year: 2023, Volume and Issue: 86(2), P. 264 - 275

Published: Jan. 18, 2023

In this study, an integrated in silico–in vitro approach was employed to discover natural products (NPs) active against SARS-CoV-2. The two SARS-CoV-2 viral proteases, i.e., main protease (Mpro) and papain-like (PLpro), were selected as targets for the silico study. Virtual hits obtained by docking more than 140,000 NPs NP derivatives available in-house from commercial sources, 38 virtual experimentally validated using enzyme-based assays. Five inhibited enzyme activity of Mpro 60% at a concentration 20 μM, four them with high potency (IC50 < 10 μM). These hit compounds further evaluated their antiviral Calu-3 cells. results cell-based assay revealed three mulberry Diels–Alder-type adducts (MDAAs) Morus alba pronounced anti-SARS-CoV-2 activities. Sanggenons C (12), O (13), G (15) showed IC50 values 4.6, 8.0, 7.6 μM selectivity index 5.1, 3.1 6.5, respectively. poses MDAAs proposed butterfly-shaped binding conformation, which supported saturation transfer difference NMR experiments competitive 1H relaxation dispersion spectroscopy.

Language: Английский

A practical guide to machine-learning scoring for structure-based virtual screening DOI
Viet‐Khoa Tran‐Nguyen, Muhammad Junaid, Saw Simeon

et al.

Nature Protocols, Journal Year: 2023, Volume and Issue: 18(11), P. 3460 - 3511

Published: Oct. 16, 2023

Language: Английский

Citations

41
Advancements in small molecule drug design: A structural perspective DOI Creative Commons
Ke Wu,

Eduard Karapetyan,

John V. Schloss

et al.

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(10), P. 103730 - 103730

Published: Aug. 1, 2023

Language: Английский

Citations

37
Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives DOI Creative Commons
Andrea Citarella, Alessandro Dimasi, Davide Moi

et al.

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

Citations

28
Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors DOI Creative Commons
Elissa A. Fink, Conner Bardine, Stefan Gahbauer

et al.

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

Citations

24
Identification of Natural Products Inhibiting SARS-CoV-2 by Targeting Viral Proteases: A Combined in Silico and in Vitro Approach DOI Creative Commons
Andreas Wasilewicz, Benjamin Kirchweger, Denisa Bojková

et al.

Journal of Natural Products, Journal Year: 2023, Volume and Issue: 86(2), P. 264 - 275

Published: Jan. 18, 2023

In this study, an integrated in silico–in vitro approach was employed to discover natural products (NPs) active against SARS-CoV-2. The two SARS-CoV-2 viral proteases, i.e., main protease (Mpro) and papain-like (PLpro), were selected as targets for the silico study. Virtual hits obtained by docking more than 140,000 NPs NP derivatives available in-house from commercial sources, 38 virtual experimentally validated using enzyme-based assays. Five inhibited enzyme activity of Mpro 60% at a concentration 20 μM, four them with high potency (IC50 < 10 μM). These hit compounds further evaluated their antiviral Calu-3 cells. results cell-based assay revealed three mulberry Diels–Alder-type adducts (MDAAs) Morus alba pronounced anti-SARS-CoV-2 activities. Sanggenons C (12), O (13), G (15) showed IC50 values 4.6, 8.0, 7.6 μM selectivity index 5.1, 3.1 6.5, respectively. poses MDAAs proposed butterfly-shaped binding conformation, which supported saturation transfer difference NMR experiments competitive 1H relaxation dispersion spectroscopy.

Language: Английский

Citations

23