A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0
Abstract
:1. Introduction
2. Results
2.1. Overview of the Available Data on SARS-CoV-2 Binding Pockets
2.2. Pockets 2.0 Performances
3. Materials and Methods
3.1. Protein Structures
3.2. Preliminary Simulations
3.3. The Pockets 2.0 Approach
3.4. Pocket Search and Analyses
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
3WL | 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one |
4VA | (2S)-4-amino-N-[(1R)-1-(4-chloro-2-fluoro-3-phenoxyphenyl)propyl]-4-oxobutan-2-aminium |
5GP | guanosine-5’-monophosphate |
77Z | 2-({(3R)-3-[(3S)-1-(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl]-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl}oxy)acetamide |
ACE2 | angiotensin-converting enzyme 2 |
AG7 | 4-{2-(4-fluoro-benzyl)-6-methyl-5-[(5-methyl-isoxazole-3-carbonyl)-amino]-4-oxo-heptanoylamino}-5-(2-oxo-pyrrolidin-3-yl)-pentanoic acid ethyl ester |
C5P | cytidine-5’-monophosphate |
G3A | guanosine-P3-adenosine-5’,5’-triphosphate |
GTA | P1-7-methylguanosine-P3-adenosine-5’,5’-triphosphate |
HCV | Hepatitis C virus |
K22 | (Z)-N-(3-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)-3-oxo-1-phenylprop-1-en-2-yl) benzamide |
MERS-Cov | Middle-East Respiratory Syndrome Coronavirus |
MGT | 7N-methyl-8-hydroguanosine-5’-triphosphate |
N7-MTase | N-7 Methyl transferase |
NSP | Non-structural protein |
ORF | Opening Reading frame |
P34 | 2-(dimethylamino)-N-(6-oxo-5H-phenanthridin-2-yl)acetamide (PJ34) |
PFI | (6S)-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2h-pyran-2-one |
PL-Pro | Papain-like protease |
POO | 3-cyclohexyl-1-(2-{methyl[(1-methylpiperidin-3-yl)methyl]amino}-2-oxoethyl)-2-phenyl 1H-indole-6-carboxylic acid |
RBD | receptor binding domain |
RdRp | RNA-dependent RNA polymerase |
SAH | S-Adenosyl homocysteine |
SAM | S-Adenosyl methionine |
SARS-CoV | Severe acute respiratory syndrome coronavirus |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
TTT | 5-amino- 2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide |
U3P | uridine-3’-monophosphate |
U5P | uridine-5’-monophosphate |
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Protein | Source a | Function | Reference Protein | PDB Id | Site | Ligand c | Ref. |
---|---|---|---|---|---|---|---|
3CL-PRO | See Table 2 | protease | ---b | ---b | orthosteric | 3WL | [15,16] |
N-Protein | 6M3M 6VYO | Nucleocapsid protein | HCoV-OC43 N-NTD | 4LMC | orthosteric | C5P | [17] |
4LM9 | 5GP | ||||||
4LM7 | U5P | ||||||
4LI4 | AMP | ||||||
4KXJ | P34 | ||||||
Nsp3 | 6W02 | ADP ribose phosphatase | --- | --- | orthosteric | ADP | *** d |
Nsp6 | DN | Membrane-spanning protein | No experimental information apart from mutants analysis | --- | allosteric | K22 | [18] |
Nsp9 | 6W4B | Replicase | Coronavirus NSP9 | 1QZ8 | orthosteric | SO4 | [19] |
Type 2 rhinovirus 3C protease | 1CQQ | orthosteric | AG7 | [20] | |||
Nsp12 | 7BV2 | RNA-dependent RNA polymerase (RdRp) | --- | --- | orthosteric | F86 | *** |
Hepatitis C RdRp | 2BRL | allosteric1 (thumb) | POO | [21] | |||
Hepatitis C NS5B polymerase | 2HAI | alllosteric2 (thumb) | PFI | [22] | |||
Hepatitis C NS5 polymerase | 3HHK | allosteric3 (palm) | 77Z | [23] | |||
Nsp13 | HM | Helicase | RNA-Dependent ATPase Upf1 | 2XZL | orthosteric | ADP-ALF | [24] |
Hepatitis C virus NS3 protein | 4B75 | Allosteric | 4VA | [25] | |||
Nsp14 | HM | Methyltransferase | SARS-CoV | 5C8S | orthosteric | SAH, G3A | [26] |
Nsp15 | 6W01 | Endoribonuclease | SARS-CoV | 2H85 | orthosteric | U3M | [27] |
Nsp16 | 6WKS 6W4H | Methyltransferase | --- | --- | orthosteric | SAM, GTA | *** |
PL-pro | 6W9C | Papain-like protease | SARS-CoV | 3E9S | orthosteric | TTT | *** |
Spike | Xray with ACE2 | Viral entry glycoprotein | --- | --- | Protein–protein interaction | YMZ | [28,29,30,31,32,33,34,35,36] |
Protein | Protein Data | Data for the Search of the Correct Pocket | ||||||
---|---|---|---|---|---|---|---|---|
Source/ID | Ligand | N Pockets | Rank by Fpocket | Rank by PLANTS | Rank by Consensus | Volume (Å3) | ChemPLP (kcal/mol) | |
3CL-PRO | 5R7Y | 3WL | 16 | 1 | 1 | 1 | 3604.93 | −76.15 |
5R7z | 3WL | 16 | 1 | 1 | 1 | 4246.06 | −73.85 | |
5R80 | 3WL | 20 | 2 | 2 | 1 | 1833.23 | −76.48 | |
5R81 | 3WL | 17 | 1 | 1 | 1 | 3141.06 | −80.27 | |
5R82 | 3WL | 19 | 1 | 4 | 1 | 3989.84 | −68.23 | |
5R83 | 3WL | 21 | 1 | 1 | 1 | 4079.17 | −77.59 | |
5R84 | 3WL | 21 | 1 | 1 | 1 | 2562.02 | −80.88 | |
6LU7 | 3WL | 14 | 1 | 1 | 1 | 4239.62 | −77.83 | |
6MN2 dimer | 3WL | 80 | 1 | 1 | 1 | 3344.72 | −86.30 | |
6M03 | 3WL | 24 | 3 | 3 | 3 | 2175.81 | −69.70 | |
6Y2E | 3WL | 18 | 1 | 4 | 1 | 2629.29 | −75.02 | |
6Y2F | 3WL | 20 | 1 | 1 | 1 | 2581.33 | −77.61 | |
6Y2G | 3WL | 16 | 2 | 3 | 2 | 5074.55 | −75.78 | |
6Y84 | 3WL | 20 | 1 | 2 | 1 | 3068.30 | −73.94 | |
Nsp3 | 6W02 | APR | 6 | 2 | 1 | 1 | 2247.84 | −119.05 |
Nsp6 | DN | K22 | 25 | 3 | 1 | 1 | 2364.82 | −75.26 |
DN | 27 | 4 | 1 | 1 | 3692.30 | −76.86 | ||
Nsp9 | 6W4B | AG7 | 13 | 2 | 3 | 1 | 2740.53 | −97.41 |
Nsp12-Nsp7-Nsp8 | 7BV2 trimer | ATP (ortho) | 79 | 1 | 2 | 1 | 4397.28 | −94.18 |
POO/ PFI (allo) | 2 | 1 | 1 | 3545.24 | −97.80 | |||
77Z (allo) | 1 | 4 | 2 | 4397.28 | −85.22 | |||
Nsp13 | HM | ADP (ortho) | 40 | 3 | 2 | 2 | 4359.36 | −79.98 |
4VA (allo) | 5 | 10 | 5 | 2526.96 | −74.28 | |||
Nsp14-Nsp10 | HM dimer | SAH | 49 | 2 | 9 | 4 | 5307.98 | −80.25 |
SAM | 2 | 2 | 1 | 5307.98 | −88.09 | |||
G3A | 2 | 1 | 1 | 5307.98 | −119.09 | |||
Nsp15 | 6W01 hexamer | U3P | 170 | 5 | 3 | 1 | 2792.58 | −80.39 |
6VWW dimer | U3P | 52 | 6 | 1 | 3 | 2275.76 | −81.75 | |
Nsp16-Nsp10 | 6WKS dimer | SAM | 63 | 1 | 8 | 1 | 4772.88 | −88.43 |
GTA | 1 | 1 | 1 | 4772.88 | −118.80 | |||
6W4H dimer | SAM | 31 | 1 | 1 | 1 | 3243.06 | −87.81 | |
GTA | 1 | 2 | 1 | 3243.06 | −112.33 | |||
N-protein | 6M3M | C5P, 5GP, U5P, AMP, P34 | 7 | 3 | 2 | 2 | 1252.56 | −66.69 |
6VYO | 7 | 3 | 3 | 3 | 1961.99 | −70.57 | ||
PL-Pro | 6W95 | TTT | 23 | 3 | 2 | 1 | 2134.23 | −94.17 |
SPIKE–ACE2 | 6LZG dimer | YMZ | 56 | 2 | 2 | 1 | 4792.66 | −80.66 |
6M0J dimer | 58 | 1 | 5 | 1 | 4407.92 | −74.29 | ||
6M17 hexamer | 275 | 1 11 | 1 1 | 1 2 | 3767.99 | −81.79 | ||
6VW1 dimer | 61 | 1 | 2 | 1 | 4920.74 | −77.78 | ||
Correctly Identified Pockets | 20 | 18 | 30 | |||||
Correct Pockets Ranked as #2 | 9 | 10 | 5 | |||||
Correct Pockets Ranked as #3 | 6 | 5 | 3 | |||||
Correct Rockets Out of the Podium | 5 | 7 | 2 | |||||
Average Rank | 2.18 | 2.43 | 1.45 | |||||
Precision | 0.5 | 0.45 | 0.75 | |||||
Accuracy | 0.97 | 0.97 | 0.99 | |||||
MCC | 0.48 | 0.43 | 0.74 |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Gervasoni, S.; Vistoli, G.; Talarico, C.; Manelfi, C.; Beccari, A.R.; Studer, G.; Tauriello, G.; Waterhouse, A.M.; Schwede, T.; Pedretti, A. A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0. Int. J. Mol. Sci. 2020, 21, 5152. https://doi.org/10.3390/ijms21145152
Gervasoni S, Vistoli G, Talarico C, Manelfi C, Beccari AR, Studer G, Tauriello G, Waterhouse AM, Schwede T, Pedretti A. A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0. International Journal of Molecular Sciences. 2020; 21(14):5152. https://doi.org/10.3390/ijms21145152
Chicago/Turabian StyleGervasoni, Silvia, Giulio Vistoli, Carmine Talarico, Candida Manelfi, Andrea R. Beccari, Gabriel Studer, Gerardo Tauriello, Andrew Mark Waterhouse, Torsten Schwede, and Alessandro Pedretti. 2020. "A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0" International Journal of Molecular Sciences 21, no. 14: 5152. https://doi.org/10.3390/ijms21145152
APA StyleGervasoni, S., Vistoli, G., Talarico, C., Manelfi, C., Beccari, A. R., Studer, G., Tauriello, G., Waterhouse, A. M., Schwede, T., & Pedretti, A. (2020). A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0. International Journal of Molecular Sciences, 21(14), 5152. https://doi.org/10.3390/ijms21145152