In Silico Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review
Abstract
1. Introduction
1.1. The Main Protease (Mpro) Enzyme of SARS-CoV-2
1.2. The Need for Novel Inhibitors
1.3. The Role of Drug Repurposing
2. Mpro Inhibitors for SARS-CoV-2
2.1. Overview of Mpro Inhibitors
2.2. Discovery Strategies for Non-Covalent Inhibitors of Mpro
2.3. Computer-Aided Drug Design
2.4. Molecular Dynamics (MD) in Drug Development
2.5. Leveraging Quantum Mechanics for ADME-Optimised Drugs
3. Summary and Outlook
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Inhibitor | Structure | Strategies for the Discovery of Non-Covalent Mpro Inhibitors | Mpro IC50 (μm) | Ref. |
---|---|---|---|---|
S-217622 | Docking-based virtual screening followed by biological screening using an in-house compound library. | 0.013 | [17] | |
Mprosevir (WU-04) | DNA-encoded library screening. | 0.072 | [44] | |
ML188 | Structure-based drug design generated through the Ugi reaction. | 2.5 | [32] | |
23R | Coupling structure-based drug design with the one-pot Ugi four-component reaction. | 0.20 | [46] | |
CCF981 | Structure-based optimisations. | 0.068 | [16] | |
N-substituted isatin derivative compound 26 | In-house synthetic compound library screening. | 0.045 | [43] | |
Benzoxaborole-based inhibitor compound 18 | Biochemical assay screenings. | 6.1 | [47] | |
9,10-dihydrophenanthrene derivatives C1 C2 | Fluorescence resonance energy transfer (FRET) biochemical assay. | 1.55 1.81 | [48] | |
HL-3-68 | Large-scale virtual screening and structural optimisation. | 0.29 | [49] | |
Mcule-CSR-494190-S1 | Large-scale virtual screening with structural optimisation. | 0.29 | [41] | |
GC-14 | Structure-based rational design combined with multi-site binding and privileged structure assembly strategies. | 0.40 | [50] | |
Imidazolidine-2,4-dione-based inhibitor compound 19 | Virtual screening combined with structural optimisation. | 0.077 | [51] | |
Walrycin B | High-throughput screening (HTS) using FRET assays. | 0.26 | [52] | |
Quinazoline derivative QZ4 | Small in-house library screening using a GFP cell-based assay. | 6.5 | [53] | |
Masitinib | Cell-based HTS. | 2.5 | [54] | |
Z-DQMD-FMK | Machine learning-driven virtual screening. | 0.92 | [55] | |
Z4927220858 | Deep docking methods. | ~10 | [56] |
Inhibitor | Structure | IC50 (µm) |
---|---|---|
Lopinavir+Ritonavir | 10.9 | |
Ritonavir | 13.7 | |
Darunavir | 36.1 | |
Atazanavir | 60.7 | |
Lopinavir | Indeterminable |
Inhibitor | Structure | Strategies for the Discovery of Non-Covalent Mpro Inhibitors | Mpro IC50 (μm) |
---|---|---|---|
Shikonin | High-throughput screening. | 0.397 | |
Quercetin | In vitro screening. | 7.4 192 | |
Selenoquercetin analogues compound 2d | Screening a small library of flavonols and flavone derivatives. | 8 | |
Baicalein | Enzymatic assays and a phenotypic assay using Vero E6 cells. | 0.39 | |
Calycosin-7-O-β-glucopyranoside | The structure-based 3D pharmacophore model was examined by induced-fit molecular docking. | 0.549 |
Compound | MolDock Score | HBond Score |
---|---|---|
N3 (Reference) | −162.17 | −8.19 |
Nelfinavir | −147.38 | −6.87 |
Hesperidin | −178.59 | −20.26 |
Rutin | −176.27 | −21.24 |
Diosmin | −174.13 | −27.26 |
Apigenin | −171.01 | −10.19 |
Complexes | ΔEele a | ΔEvdW b | ΔGpol c | ΔGnonpol d | ΔGcalc e |
---|---|---|---|---|---|
Z1244904919-Mpro | –18.76 | –46.88 | –65.63 | –3.81 | –45.72 |
Z1759961356-Mpro | –6.03 | –52.51 | –58.54 | –4.25 | –48.01 |
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Alagawani, I.; Wang, F. In Silico Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review. Appl. Sci. 2025, 15, 6544. https://doi.org/10.3390/app15126544
Alagawani I, Wang F. In Silico Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review. Applied Sciences. 2025; 15(12):6544. https://doi.org/10.3390/app15126544
Chicago/Turabian StyleAlagawani, Islam, and Feng Wang. 2025. "In Silico Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review" Applied Sciences 15, no. 12: 6544. https://doi.org/10.3390/app15126544
APA StyleAlagawani, I., & Wang, F. (2025). In Silico Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review. Applied Sciences, 15(12), 6544. https://doi.org/10.3390/app15126544