A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework
Abstract
:1. Introduction
2. Results
2.1. Drugs, Protein Targets, and PDB Structures Included in This Study
2.2. TDA Results, Viral Proteins Showing Mean Persistent Similarities above 0.9 with Structures Targeted by Known FDA-Approved Drugs
2.3. Transcriptomic Data Analysis Results
2.4. GSEA Analysis of the Repurposing Candidates
3. Discussion
4. Materials and Methods
4.1. Data Acquisition
4.2. A Topological Data Analysis Based Formalism to Compare, at Quantitative Level, the Homological Similarities of Pairwise Three-Dimensional Molecules Considered as Surfaces
4.3. Data Preprocessing and Persistent Similarity Measures Computation
4.4. Protein–Ligand Binding with AutoDock 4.2
4.5. Differential Gene Expression Analyses of SARS-CoV-2 Infected Human Samples and Cell Lines and Uninfected Controls
4.6. Identification of LINCS 1000 Signatures Negatively Correlated with the SARS-CoV-2 Differential Gene Expression Profiles
4.7. Gene Set Enrichment Analysis (GSEA)
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Entry ID | Structure Title | Macromolecule Name | Chain ID |
---|---|---|---|
6LVN | 2019-nCoV HR2 Domain | Spike protein S2 | A, B, C, D |
6YI3 | The N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein | Nucleoprotein | A |
6M3M | SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain | SARS-CoV-2 nucleocapsid protein | A, B, C, D |
6VYO | RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2 | Nucleoprotein | A, B, C, D |
6WJI | C-terminal Dimerization Domain of Nucleocapsid Phosphoprotein from SARS-CoV-2 | SARS-CoV-2 nucleocapsid protein | A, B, C, D, E, F |
6LXT | Structure of post fusion core of 2019-nCoV S2 subunit | Spike protein S2 | A, B, C, D, E, F |
6VSB | Prefusion 2019-nCoV spike glycoprotein with a single receptor-binding domain up | SARS-CoV-2 spike glycoprotein | A, B, C |
6VYB | SARS-CoV-2 spike ectodomain structure (open state) | Spike glycoprotein | A, B, C |
6W41 | Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022 | CR3022 Fab heavy chain | H |
CR3022 Fab light chain | L | ||
Spike protein S1 | C | ||
6YLA | Crystal structure of the SARS-CoV-2 receptor binding domain in complex with CR3022 Fab | Spike glycoprotein | A, E |
Heavy Chain | B, H | ||
Light chain | C, L | ||
6M0J | Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2 | Angiotensin converting enzyme 2 | A |
Spike receptor binding domain | E | ||
6M17 | 2019-nCoV RBD/ACE2-B0AT1 complex | Sodium-dependent neutral amino acid transporter B(0)AT1 | A, C |
Angiotensin converting enzyme 2 | B, D | ||
SARS-coV-2 Receptor Binding Domain | E, F | ||
6M2Q | SARS-CoV-2 3CL protease (3CL pro) apo structure (space group C21) | SARS-CoV-2 3CL protease | A |
6W4B | Crystal structure of Nsp9 RNA binding protein of SARS CoV-2 | Non-structural protein 9 | A, B |
6W9Q | Peptide-bound SARS-CoV-2 Nsp9 RNA replicase | 3C-like proteinase peptide, Nonstructural protein 9 fusion | A |
6VXS | Crystal Structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 | Non-structural protein 3 | A, B |
6W9C | Crystal structure of papain-like protease of SARS CoV-2 | Papain-like proteinase | A, B, C |
6WCF | Crystal Structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES | Non-structural protein 3 | A |
6WEN | Crystal Structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in the apo form | Non-structural protein 3 | A |
6WIQ | Crystal structure of the co-factor complex of NSP7 and the C-terminal domain of NSP8 from SARS CoV-2 | SARS-CoV-2 NSP7 | A |
SARS-CoV-2 NSP8 | B | ||
6M71 | SARS-Cov-2 RNA-dependent RNA polymerase in complex with cofactors | SARS-Cov-2 NSP 12 | A |
SARS-Cov-2 NSP 8 | C | ||
SARS-Cov-2 NSP 7 | B, D | ||
6W01 | 1.9 A Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with a Citrate | Uridylate-specific endoribonuclease | A, B |
6VWW | Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 | Uridylate-specific endoribonuclease | A, B |
6M2Q (SARS-CoV-2 3CL Protease) | ||||||
---|---|---|---|---|---|---|
Drug Name | Drug ID | PC DS1 (GSE150316) | PC DS2 (CRA002390) | PC DS3 (GSE147507) | AutoDock LE (kcal/mol) | AutoDock Cluster |
CholicAcid | DB02659 | −0.09 | −0.11 | −0.08 | −15.06 | 74 |
Rutin | DB01698 | −0.07 | −0.18 | −0.1 | −14.52 | 149 |
Indomethacin | DB00328 | −0.07 | −0.12 | −0.05 | −13.31 | 146 |
Sulindac | DB00605 | −0.07 | −0.12 | −0.07 | −13.14 | 73 |
Sulfisoxazole | DB00263 | −0.05 | −0.13 | −0.09 | −11.59 | 77 |
Dasatinib | DB01254 | −0.04 | −0.15 | −0.09 | −10.94 | 43 |
6W01 (NSP15 Endoribonuclease) | ||||||
Dexamethasone | DB01234 | −0.07 | −0.15 | −0.08 | −11.42 | 49 |
Phenolphthalein | DB04824 | −0.13 | −0.1 | −0.04 | −11.15 | 101 |
Spironolactone | DB00421 | −0.12 | −0.1 | −0.09 | −10.99 | 110 |
Mifepristone | DB00834 | −0.13 | −0.14 | −0.06 | −10.04 | 28 |
Carbamazepine | DB00564 | −0.08 | −0.14 | −0.07 | −9.66 | 86 |
6M71 (NSP12 RNA-dependent RNA polymerase) | ||||||
Vemurafenib | DB08881 | −0.09 | −0.16 | −0.08 | −8.09 | 13 |
Sorafenib | DB00398 | −0.11 | −0.15 | −0.05 | −7.34 | 30 |
Levonorgestrel | DB00367 | −0.08 | −0.14 | −0.08 | −7.21 | 89 |
Naloxone | DB01183 | −0.06 | −0.12 | −0.09 | −7.07 | 69 |
Raloxifene | DB00481 | −0.13 | −0.17 | −0.07 | −7.05 | 6 |
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Pérez-Moraga, R.; Forés-Martos, J.; Suay-García, B.; Duval, J.-L.; Falcó, A.; Climent, J. A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework. Pharmaceutics 2021, 13, 488. https://doi.org/10.3390/pharmaceutics13040488
Pérez-Moraga R, Forés-Martos J, Suay-García B, Duval J-L, Falcó A, Climent J. A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework. Pharmaceutics. 2021; 13(4):488. https://doi.org/10.3390/pharmaceutics13040488
Chicago/Turabian StylePérez-Moraga, Raul, Jaume Forés-Martos, Beatriz Suay-García, Jean-Louis Duval, Antonio Falcó, and Joan Climent. 2021. "A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework" Pharmaceutics 13, no. 4: 488. https://doi.org/10.3390/pharmaceutics13040488