Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro
Abstract
:1. Introduction
2. Results
2.1. ADMET Analysis by QikPropTM
2.2. Toxicological Analysis by Derek NexusTM
2.3. Site Prediction and Druggability Analysis of SARS-CoV-2 Mpro
2.4. Molecular Docking Simulations
2.5. Molecular Dynamics (MD) Simulations
3. Discussion
4. Materials and Methods
4.1. SARS-CoV-2 Mpro Protein Preparation
4.2. Site Prediction and Druggability Analysis of SARS-CoV-2 Mpro
4.2.1. SeeSAR
4.2.2. PockDrug
4.2.3. FTMap
4.2.4. Molecular Docking on SARS-CoV-2 Mpro
4.2.5. SARS-CoV-2 Ligand Preparation
4.2.6. ADMET Analysis by QikPropTM and DerekTM
4.2.7. Molecular Dynamics (MD) Simulations on SARS-CoV-2 Mpro-NatProDB Complexes
4.2.8. Hydrogen Bond Capacity Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
COVID-19 | Coronavirus disease 2019 |
SARS-CoV-2 | severe acute respiratory syndrome coronavirus 2 |
ACE2 | angiotensin-converting enzyme |
ADMET | absorption, distribution, metabolism, and excretion/toxicity |
MD | molecular dynamics |
NatProDB | Natural Products Database of the Bahia Semi-Arid region |
3CLpro | SARS-CoV-2 Main Protease |
CoVs | coronaviruses |
PDB | Protein Data Bank |
PSA | polar surface area |
%HOA | human oral absorption in percentage |
QPlogPo/w | logarithm of the partition coefficient in 1-octanol/water predicted by QikProp |
QPLogBB | logarithm of the blood–brain barrier predicted by QikProp |
QPPCaco | permeability across Caco-2 cells predicted by QikProp |
CNS | central nervous system |
RMSF | root-mean square fluctuation |
LogKhsa | logarithmic human serum albumin-binding predicted by QikProp |
EA | estimated affinities |
Hbondcapac. | hydrogen bond capability |
ΔEbinding | binding energy |
QPPMDCK | permeability across Madin-Darby Canine Kidney cells predicted by QikProp |
MW | molecular weight |
HTS | high-throughput screening |
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# | Compounds | Chemical Structure | Hydrogen Bond Donors (HBD) 1 | Hydrogen Bond Acceptors (HBA) | Lipinki’s Rule 2 Violation | Molecular Surface Area (Å2) 3 | Solvent Accessible Surface (Å3) 4 | Estimated Affinity Range 5 (µM) | Inter Clash Type 6 |
---|---|---|---|---|---|---|---|---|---|
b01 | VE0DIA0AF | 1 | 2 | 1 | 134.92 | 478.2 | 3.29–326.4 | + | |
b02 | VE0PPA0AF | 5 | 5 | 0 | 150.25 | 481.3 | 4.42–439.6 | 0 | |
b03 | VE0ISA0AF | 1 | 5 | 0 | 152.87 | 645.3 | 7.24–719.2 | + | |
b04 | VE0FKA0AF | 2 | 5 | 0 | 150.34 | 576.2 | 17.25–1714.3 | + | |
b05 | VE0FEA0SF | 4 | 6 | 0 | 150.17 | 519.5 | 18.18–1806.5 | 0 | |
b06 | VE0JDA0SF | 3 | 5 | 0 | 121.72 | 355.9 | 20.82–2068.7 | 0 | |
b07 | VE0ZDA0AF | 1 | 5 | 0 | 151.74 | 652.2 | 41.3–4103.0 | + | |
b08 | VE0NCA0SF | 1 | 2 | 0 | 72.59 | 309.2 | 51.97–5164.2 | + | |
b09 | VE0KJA0SI | 3 | 8 | 0 | 148.67 | 599.8 | 52.40–5206.5 | 0 | |
b10 | VE0NHA0SF | 3 | 6 | 0 | 122.04 | 543.6 | 53.85–5350.2 | + | |
255Control(RZS) | - | 1 | 3 | 0 | 65.69 | 350.4 | 504.29–50,103.8 | + | |
562Positive control(E-64) | - | 7 | 10 | 1 | 145.91 | 638.3 | 96,164.969, 455,201.9 | 0 |
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Silva, R.C.; Freitas, H.F.; Campos, J.M.; Kimani, N.M.; Silva, C.H.T.P.; Borges, R.S.; Pita, S.S.R.; Santos, C.B.R. Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro. Int. J. Mol. Sci. 2021, 22, 11739. https://doi.org/10.3390/ijms222111739
Silva RC, Freitas HF, Campos JM, Kimani NM, Silva CHTP, Borges RS, Pita SSR, Santos CBR. Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro. International Journal of Molecular Sciences. 2021; 22(21):11739. https://doi.org/10.3390/ijms222111739
Chicago/Turabian StyleSilva, Rai C., Humberto F. Freitas, Joaquín M. Campos, Njogu M. Kimani, Carlos H. T. P. Silva, Rosivaldo S. Borges, Samuel S. R. Pita, and Cleydson B. R. Santos. 2021. "Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro" International Journal of Molecular Sciences 22, no. 21: 11739. https://doi.org/10.3390/ijms222111739