Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin
Abstract
:1. Introduction
2. Results and Discussion
2.1. Description of Binding Sites of Mpro and RBD Structures
2.1.1. Binding Site Analysis of Mpro
2.1.2. Binding Site Analysis of RBD
2.2. Virtual Screening Studies
2.2.1. Molecular Docking Studies
Molecular Docking Studies of Mpro
Molecular Docking Studies of RBD
Shortlisted Compounds for Downstream Analysis
2.2.2. Characterization of the Protein–Ligand Interactions
Characterization of the Mpro–Ligand Interactions
Characterization of the RBD–Ligand Interactions
2.2.3. Predictions of Biological Activities
2.3. Existing Drugs Proposed as Potential Frontline Treatment Options
2.3.1. Similarity Search of Hits
2.3.2. Fusidic Acid and Betulinic Acid as Potential Anti-SARS-CoV-2 Compounds
2.4. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) Calculations
2.4.1. MM/PBSA-Binding Free Energy Computational Analysis of Mpro
2.4.2. MM/PBSA-Binding Free Energy Computational Analysis of RBD
2.5. Other Contributing Energy Terms
2.5.1. Energy Decomposition per Residue
Per-Residue Energy Decomposition of Mpro–Ligand Complexes
Per-Residue Energy Decomposition of the RBD–Ligand Complexes
2.6. Molecular Dynamics
2.6.1. Root Mean Square Deviation of the Complexes for 100 ns MD Simulations
2.6.2. Root Mean Square Fluctuation of the Complexes for 100 ns MD Simulations
2.6.3. Radius of Gyration of the Complexes for 100 ns MD Simulations
2.7. Comparison of Binding Modes Pre-MD and Post-100 ns MD Simulations
2.7.1. Binding Modes Interactions Analysis between Mpro and Potential Leads
2.7.2. Binding Modes Interactions Analysis between RBD and Potential Leads
2.8. Summary and Implications of the Results
3. Materials and Methods
3.1. Data Sources for SARS-CoV-2 Targets
3.2. The Screening Library
3.3. Preparation of the Protein Structure and Elucidation-Binding Sites
3.4. Virtual Screening of Ligand Library
3.5. Characterization of the Protein–Ligand Interactions
3.6. Prediction of Antiviral Properties of Hit Compounds
3.7. Molecular Dynamics Simulation of Protein–Ligand Complexes
3.8. Analysis of Binding Modes
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Pocket Area (Å2) | Volume (Å3) | Residues Lining Pockets | |
---|---|---|---|
Mpro | |||
1 | 557.1 | 920.6 | Thr24, Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49, Leu50, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, Leu167, Pro168, Asp187, Arg188, Gln189, Thr190, Gln192 |
2 | 380.0 | 465.1 | Met6, Ala7, Phe8, Pro9, Gly11, Lys12, Val13, Gln127, Phe150, Ile152, Asp153, Tyr154, Val157, Phe291, Asp295, Arg298, Gln299, Val303, Thr304 |
3 | 107.5 | 151.3 | Phe3, Arg4, Lys5, Trp207, Leu282, Ser284, Glu288, Phe291 |
4 | 193.5 | 225.2 | Pro108, Gly109, Gln110, Pro132, Ile200, Thr201, Val202, Asn203, Glu240, His246, Ile249, Thr292, Pro293, Phe294 |
5 | 86.6 | 131.4 | Glu14, Gly15, Met17, Val18, Trp31, Ala70, Gly71, Val73, Asn95, Lys97 |
RBD | |||
A | 148.3 | 169.2 | Arg454, Phe456, Arg457, Lys458, Asp467, Ser469, Glu471, Ile472, Tyr473, Pro491 |
B | 52.3 | 90.3 | Phe342, Asn343, Leu368, Ser371, Ser373, Phe374 |
C | 146.8 | 160.6 | Glu340, Val341, Ala344, Arg346, Phe347, Ala348, Asn354, Arg355, Lys356, Ala397, Ser399, Val511 |
Compound | Source | Binding Energy (kcal/mol) | Hydrogen Bonds [Bond Length (Ȧ)] | Hydrophobic Bonds | |||
---|---|---|---|---|---|---|---|
Mpro | RBD | Mpro | RBD | Mpro | RBD | ||
Selected Hits | |||||||
NANPDB2403 | ANC | −8.1 | −7.8 | Leu287 (3.22) | - | Thr199, Tyr237, Tyr239, Leu271, Leu272, Leu286. | Leu335, Cys336, Phe338, Phe342, Asn343, Asp364, Val367, Leu368, Ser371, |
NANPDB2245 | ANC | −8.0 | −7.7 | Arg131 (2.92) | Asn343 (2.96) | Lys137, Thr199, Tyr237, Tyr239, Leu271, Leu272, Leu286, Leu287, Asp289 | Leu335, Cyc336, Phe338, Gly339, Asp364, Val367, Leu368, Ser371, Phe374 |
ZINC000055656943 | ML | −8.0 | −8.0 | Asp197 (2.80) | - | Arg131, Thr198, Thr199, Tyr237, Tyr239, Leu272, Leu287 | Leu335, Cys336, Phe338, Phe342, Asp364, Val367, Leu368, Ser371, Phe374, |
ZINC000095486008 | ANC | −8.2 | −7.8 | Lys5 (3.1), Glu288 (3.02) | Cys336 (2.96), Phe338 (3.26), Gly339 (3.3) | Lys137, Asp197, Thr199, Tyr239, Leu272, Leu286, Leu287, Asp289, Glu290 | Pro337, Phe342, Asn343, Val367, Leu368, Ser371, Phe374, Trp436 |
ZINC001645993538 | ML | −7.7 | −7.5 | Thr199 (314) | - | Lys137, Asp197, Tyr239, Leu272, Leu286, Leu287, Glu288, Asp289 | Cys336, Phe338, Asp364, Val367, Leu368, Ser371, Phe374 |
Known Antivirals and Experimental Drugs | |||||||
Oxymetholone | −7.8 | −7.7 | Thr25 (2.81), Glu166 (2.9, 3.00) | Cys336 (3.0), Asn343 (3.09) | His41, Ser46, Thr45, Asn142, Gly143, Cys145, His164, Met165 | Leu335, Phe338, Gly339, Phe342, Asp364, Val367, Leu368, Ser371, Phe374 | |
Dexamethasone | −7.6 | −6.7 | Asp197 (2.9, 3.24), Met276 (3.01), Leu287 (3.29, 3.32) | Arg355 (2.99, 3.01), Thr430 (3.18), Glu516 (2.76) | Lys137, Thr198, Thr199, Tyr239, Leu271, Gly275, Leu286, Leu287, Asp289 | Pro426, Phe429, Pro463, Phe464, Phe515 | |
Remdesivir | −6.8 | −6.3 | Lys137 (3.19), Thr199 (2.82, 3.05), Leu287 (3.09), Asp289 (2.84) | Gly496 (2.84, 2.96), Asn501 (2.9) | Arg131, Asp197, Thr198, Tyr237, Asn238, Tyr239, Leu271, Leu272, Asn274, Gly275, Met276, Leu286 | Arg403, Tyr453, Leu455, Ser494, Tyr495, Phe497, Tyr505 | |
Hydroxychloroquine | −5.9 | −5.5 | Asp197 (3.05, 3.22), Thr199 (3.26) | Thr345 (2.97), Asn354 (3.04), Ala397 (2.72), Ser399 (2.99), | Arg131, Thr198, Tyr237, Tyr239, Leu272, Met276, Ala285, Leu286, Leu287, Asp289 | Glu340, Val341, Ala344, Arg346, Phe347, Ala348, Arg355, Lys356, Asp398 | |
Chloroquine | −5.5 | −4.9 | Tyr239 (3.2) | - | Arg131, Asp197, Thr198, Thr199, Tyr237, Leu272, Leu286, Leu287, Asp289, | Arg403, Tyr449, Tyr453, Ser494, Tyr495, Gly496, Phe497, Asn501, Tyr505 |
Compound | van der Waals Energy (kJ/mol) | Electrostatic Energy (kJ/mol) | Polar Solvation Energy (kJ/mol) | SASA Energy (kJ/mol) | Binding Energy (kJ/mol) |
---|---|---|---|---|---|
Mpro | |||||
NANPDB2245 | −85.61 +/− 11.970 | −6.274 +/− 7.537 | 46.495 +/− 10.814 | −10.829 +/− 1.110 | −56.223 +/− 11.988 |
NANPDB2403 | −77.965 +/− 12.063 | −6.624 +/− 7.992 | 36.397 +/− 13.775 | −9.939 +/− 1.139 | −58.132 +/− 13.000 |
ZINC000095486008 | −98.620 +/− 15.067 | −20.464 +/− 14.240 | 84.718 +/− 29.042 | −12.692 +/− 1.538 | −47.058 +/− 20.877 |
ZINC000055656943 | −18.966 +/− 26.649 | −2.907 +/− 8.983 | 7.468 +/− 57.684 | −2.692 +/− 4.061 | −17.097 +/− 45.262 |
ZINC001645993538 | −84.952 +/− 12.296 | −20.470 +/− 13.867 | 62.338 +/− 24.852 | −10.702 +/− 1.140 | −53.785 +/− 18.652 |
Oxymetholone | −60.820 +/− 13.039 | −3.207 +/− 5.288 | 27.787 +/− 20.226 | −8.485 +/− 1.967 | −44.724 +/− 17.562 |
Remdesivir | −114.276 +/− 18.798 | −19.410 +/− 12.604 | 89.056 +/− 41.414 | −13.726 +/− 2.248 | −58.356 +/− 31.051 |
RBD | |||||
NANPDB2245 | −30.310 +/− 43.669 | −2.337 +/− 4.496 | 14.435 +/− 40.707 | −3.930 +/− 5.769 | −22.142 +/− 39.775 |
NANPDB2403 | −79.080 +/− 14.764 | −2.714 +/− 7.624 | 39.552 +/− 18.265 | −10.898 +/− 1.698 | −53.140 +/− 20.905 |
ZINC000095486008 | −119.217 +/− 10.410 | −8.227 +/− 7.728 | 77.567 +/− 12.472 | −15.298 +/− 1.031 | −65.174 +/− 10.495 |
ZINC000055656943 | −58.972 +/− 54.205 | −11.991 +/− 12.656 | 34.870 +/− 57.870 | −7.003 +/− 6.417 | −43.096 +/− 39.685 |
ZINC001645993538 | −109.967 +/− 10.090 | −0.990 +/− 6.308 | 63.10 +/− 8.655 | −13.921 +/− 0.760 | −61.778 +/− 9.594 |
Oxymetholone | −109.874 +/− 9.028 | −15.240 +/− 7.816 | 74.123 +/− 15.363 | −13.752 +/− 0.876 | −64.742 +/− 14.235 |
Remdesivir | −100.708 +/− 18.622 | −11.616 +/− 11.476 | 80.060 +/− 24.762 | −12.206 +/− 1.981 | −44.471 +/− 19.222 |
Mpro | ||||
---|---|---|---|---|
Pre-MD Interactions | Post-MD Interactions (100 ns) | |||
Compound Name | H-Bond Residues | Hydrophobic Bond Residues | H-Bond Residues | Hydrophobic Bond Residues |
NANPDB2403 | Thr199, Leu287 | Tyr237, Tyr239, Leu271, Leu272, Leu286 | - | Tyr237, Leu271, Leu272, Leu287 |
ZINC95486008 | Gly5, Glu288 | Lys137, Asp197, Thr199, Tyr239, Leu272, Leu286, Leu287, Asp289, Glu290 | - | Trp31, Ala70, Gly71, Asn72, Val73, Leu75, Ala94 |
RBD | ||||
---|---|---|---|---|
Pre-MD Interactions | Post-MD Interactions (100 ns) | |||
Compound Name | H-Bond Residues | Hydrophobic Bond Residues | H-Bond Residues | Hydrophobic Bond Residues |
NANPDB2403 | - | Leu335, Cys336, Phe338, Phe342, Asn343, Asp364, Val367, Leu368, Ser371 | - | Gly339, Phe342, Val367, Ser373, Phe374 |
ZINC95486008 | Cys336, Phe338,Gly339 | Pro337, Phe342, Asn343, Val367, Leu368, Ser371, Phe374, Trp436 | Asn343 | Cys336, Gly339, Phe342, Asp364, Val367, Ser373 |
Ligand ID | Common/IUPAC Name | 2D Structure |
---|---|---|
NANPDB2245 | Helioscopinolide B | |
NANPDB2403 | Retusolide B | |
Fusidic acid | Fusidic acid | |
ZINC000095486008 | (2R,10R,18S)-17,17-dimethyl-3,16-dioxapentacyclo (1 1.8.0.02,10.04,9.015,20) henicosa-1(13),4,6,8,14,20-hexaene-6,18-diol | |
ZINC000055656943 | (4S)-7-fluoro-N-((1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide | |
ZINC001645993538 | (4S)-N-((1R,3R,6R)-7,7-difluorobicyclo (4.1.0) heptan-3-yl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide | |
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Kwofie, S.K.; Broni, E.; Asiedu, S.O.; Kwarko, G.B.; Dankwa, B.; Enninful, K.S.; Tiburu, E.K.; Wilson, M.D. Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin. Molecules 2021, 26, 406. https://doi.org/10.3390/molecules26020406
Kwofie SK, Broni E, Asiedu SO, Kwarko GB, Dankwa B, Enninful KS, Tiburu EK, Wilson MD. Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin. Molecules. 2021; 26(2):406. https://doi.org/10.3390/molecules26020406
Chicago/Turabian StyleKwofie, Samuel K., Emmanuel Broni, Seth O. Asiedu, Gabriel B. Kwarko, Bismark Dankwa, Kweku S. Enninful, Elvis K. Tiburu, and Michael D. Wilson. 2021. "Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin" Molecules 26, no. 2: 406. https://doi.org/10.3390/molecules26020406