PMC:7094172 / 24048-28114 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7094172","sourcedb":"PMC","sourceid":"7094172","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7094172","text":"Discussion and Conclusions\nThe use of small molecules to stabilize PPI interfaces has been shown to be a viable approach for the development of new therapeutics. Most compounds created by structure-based design to manipulate the PPI depend on detailed knowledge of the native interacting interfaces.35−37 In contrast, most of the compounds with therapeutic potential that stabilize non-native PPI interfaces were discovered by chance alone.38 The anti-influenza compound nucleozin was initially discovered using a chemical genetics approach, and its ability to stabilize non-native nucleoprotein oligomers was elucidated much later.39,40 Swinholide A, a cytotoxic marine macrolide, has been known to disrupt the actin cytoskeleton and act as an anticancer agent, but it took ten years to discover that it stabilized G-actin as a non-native homodimer complex.41−43 However, these examples did underscore the importance of hydrophobicity as a crucial factor stabilizing protein–protein and protein–ligand associations.44 Here, we demonstrated the possibility of using the hydrophobic interactions on non-native interfaces as targets for virtual screening. Combined with suitable selection criteria focusing on both shape and hydrophobic complementarities between the ligand and the receptor, small-molecule compounds that stabilize non-native PPIs may be identified in a rational manner. Using the above approach, we successfully identified a compound P3 that affected the biochemical activity of our target protein and showed efficacy against our target pathogen MERS-CoV (Figures 2 and 4). P3-mediated non-native MERS-CoV N-NTD dimerization induced abnormal N protein aggregation by influencing the oligomeric behavior of N-CTD and eventually halting its function in RNP formation. To the best of our knowledge, this structure-based strategy for targeting non-native interfaces has never been proposed for therapeutic design. Thus, non-native interaction interfaces in proteins may comprise a new drug development target class. For β-coronaviruses such as MERS-CoV, the amino acids comprising the non-native interaction interface on N-NTD are relatively conserved. The hydrophobic pocket surrounding W43 and F135 on monomer 1 is shared among other β-coronaviruses.24,28 The interacting surface on monomer 2, which includes G104, T105, G106, and A109, is also highly conserved (Figure S4). This conservation may provide certain advantages when developing compounds with broad-spectrum activity against a target pathogen family, including COVID-19. When we tested P3 on mouse hepatitis virus (MHV), we observed a reduction in viral titer, indicating that P3 may also inhibit MHV replication (Figure S5). On the other hand, targeting non-native interaction interfaces is not trivial. As interface formation is induced by an external agent, computations aimed at predicting native PPI structures may not be able to identify potential non-native interfaces. Nevertheless, several stratagems may assist in the identification of potential non-native interaction interfaces. One strategy is to search for target protein structures with crystal packing contacts known to be biologically irrelevant. Another approach is to identify weakly interacting sites through NMR chemical shift perturbation and hydrogen-deuterium exchange MS.45 Once these potential non-native interaction interfaces are identified, standard screening and then functional characterization may be conducted for small compounds that bind to the interface.\nTo summarize, we demonstrated that non-native interaction interfaces might form when proteins abnormally oligomerize. Using the MERS-CoV N protein as an example, we showed that non-native interfaces might serve as targets for small-molecule, structure-based screening. We also proposed several stratagems to rationally identify potential non-native interface targets for screening. We believe that we have discovered and tested an alternative drug discovery paradigm that could help expand the repertoire of lead compounds against various pathogens.","divisions":[{"label":"title","span":{"begin":0,"end":26}},{"label":"p","span":{"begin":27,"end":3516}}],"tracks":[{"project":"LitCovid-PMC-OGER-BB","denotations":[{"id":"T406","span":{"begin":2056,"end":2064},"obj":"SP_9"},{"id":"T405","span":{"begin":2250,"end":2263},"obj":"NCBITaxon:11118"},{"id":"T404","span":{"begin":2454,"end":2463},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T403","span":{"begin":2537,"end":2545},"obj":"SP_7"},{"id":"T402","span":{"begin":2568,"end":2573},"obj":"NCBITaxon:10088"},{"id":"T401","span":{"begin":2574,"end":2583},"obj":"NCBITaxon:5690"},{"id":"T400","span":{"begin":2584,"end":2589},"obj":"NCBITaxon:10239"},{"id":"T399","span":{"begin":2591,"end":2594},"obj":"NCBITaxon:11757"},{"id":"T398","span":{"begin":2624,"end":2629},"obj":"NCBITaxon:10239"},{"id":"T397","span":{"begin":2673,"end":2676},"obj":"NCBITaxon:11757"},{"id":"T396","span":{"begin":2677,"end":2688},"obj":"GO:0006260"},{"id":"T395","span":{"begin":3479,"end":3488},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T394","span":{"begin":3622,"end":3633},"obj":"GO:0051259"},{"id":"T393","span":{"begin":3645,"end":3653},"obj":"SP_9"},{"id":"T392","span":{"begin":3654,"end":3663},"obj":"PG_4"},{"id":"T391","span":{"begin":3749,"end":3757},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T390","span":{"begin":3960,"end":3964},"obj":"CHEBI:23888;CHEBI:23888"},{"id":"T389","span":{"begin":4030,"end":4039},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T424","span":{"begin":44,"end":53},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T423","span":{"begin":167,"end":176},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T422","span":{"begin":330,"end":339},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T421","span":{"begin":582,"end":595},"obj":"PG_4"},{"id":"T420","span":{"begin":671,"end":680},"obj":"CHEBI:25106;CHEBI:25106"},{"id":"T419","span":{"begin":712,"end":730},"obj":"GO:0015629"},{"id":"T418","span":{"begin":745,"end":755},"obj":"CHEBI:67079;CHEBI:67079"},{"id":"T417","span":{"begin":816,"end":817},"obj":"GO:0000811"},{"id":"T416","span":{"begin":817,"end":823},"obj":"GO:0031941"},{"id":"T415","span":{"begin":1296,"end":1314},"obj":"CHEBI:36357;CHEBI:36357"},{"id":"T414","span":{"begin":1562,"end":1570},"obj":"SP_9"},{"id":"T413","span":{"begin":1613,"end":1621},"obj":"SP_9"},{"id":"T412","span":{"begin":1628,"end":1640},"obj":"GO:0046983"},{"id":"T411","span":{"begin":1658,"end":1667},"obj":"PG_4"},{"id":"T410","span":{"begin":1767,"end":1770},"obj":"SO:0000694"},{"id":"T409","span":{"begin":1997,"end":2001},"obj":"CHEBI:23888;CHEBI:23888;GO:0017144"},{"id":"T408","span":{"begin":2002,"end":2013},"obj":"GO:0017144"},{"id":"T407","span":{"begin":2034,"end":2047},"obj":"NCBITaxon:11118"}],"attributes":[{"subj":"T406","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T405","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T404","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T403","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T402","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T401","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T400","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T399","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T398","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T397","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T396","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T395","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T394","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T393","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T392","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T391","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T390","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T389","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T424","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T423","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T422","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T421","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T420","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T419","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T418","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T417","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T416","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T415","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T414","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T413","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T412","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T411","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T410","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T409","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T408","pred":"source","obj":"LitCovid-PMC-OGER-BB"},{"subj":"T407","pred":"source","obj":"LitCovid-PMC-OGER-BB"}]},{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T121","span":{"begin":712,"end":730},"obj":"Body_part"},{"id":"T122","span":{"begin":816,"end":823},"obj":"Body_part"},{"id":"T123","span":{"begin":968,"end":975},"obj":"Body_part"},{"id":"T124","span":{"begin":976,"end":983},"obj":"Body_part"},{"id":"T125","span":{"begin":988,"end":995},"obj":"Body_part"},{"id":"T126","span":{"begin":1506,"end":1513},"obj":"Body_part"},{"id":"T127","span":{"begin":1660,"end":1667},"obj":"Body_part"},{"id":"T128","span":{"begin":1969,"end":1977},"obj":"Body_part"},{"id":"T129","span":{"begin":2070,"end":2081},"obj":"Body_part"},{"id":"T130","span":{"begin":2715,"end":2719},"obj":"Body_part"},{"id":"T131","span":{"begin":3104,"end":3111},"obj":"Body_part"},{"id":"T132","span":{"begin":3602,"end":3610},"obj":"Body_part"},{"id":"T133","span":{"begin":3656,"end":3663},"obj":"Body_part"}],"attributes":[{"id":"A121","pred":"fma_id","subj":"T121","obj":"http://purl.org/sig/ont/fma/fma84684"},{"id":"A122","pred":"fma_id","subj":"T122","obj":"http://purl.org/sig/ont/fma/fma67893"},{"id":"A123","pred":"fma_id","subj":"T123","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A124","pred":"fma_id","subj":"T124","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A125","pred":"fma_id","subj":"T125","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A126","pred":"fma_id","subj":"T126","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A127","pred":"fma_id","subj":"T127","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A128","pred":"fma_id","subj":"T128","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A129","pred":"fma_id","subj":"T129","obj":"http://purl.org/sig/ont/fma/fma82739"},{"id":"A130","pred":"fma_id","subj":"T130","obj":"http://purl.org/sig/ont/fma/fma9712"},{"id":"A131","pred":"fma_id","subj":"T131","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A132","pred":"fma_id","subj":"T132","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A133","pred":"fma_id","subj":"T133","obj":"http://purl.org/sig/ont/fma/fma67257"},{"subj":"T121","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T122","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T123","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T124","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T125","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T126","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T127","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T128","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T129","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T130","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T131","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T132","pred":"source","obj":"LitCovid-PD-FMA-UBERON"},{"subj":"T133","pred":"source","obj":"LitCovid-PD-FMA-UBERON"}]},{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T2","span":{"begin":2715,"end":2719},"obj":"Body_part"}],"attributes":[{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0002398"},{"subj":"T2","pred":"source","obj":"LitCovid-PD-UBERON"}]},{"project":"LitCovid_AGAC","denotations":[{"id":"p35904s12","span":{"begin":700,"end":707},"obj":"NegReg"},{"id":"p35904s14","span":{"begin":712,"end":730},"obj":"MPA"},{"id":"p35911s11","span":{"begin":1649,"end":1679},"obj":"MPA"},{"id":"p35918s15","span":{"begin":2611,"end":2620},"obj":"NegReg"}],"attributes":[{"subj":"p35904s12","pred":"source","obj":"LitCovid_AGAC"},{"subj":"p35904s14","pred":"source","obj":"LitCovid_AGAC"},{"subj":"p35911s11","pred":"source","obj":"LitCovid_AGAC"},{"subj":"p35918s15","pred":"source","obj":"LitCovid_AGAC"}]},{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T92","span":{"begin":452,"end":461},"obj":"Disease"},{"id":"T93","span":{"begin":1624,"end":1627},"obj":"Disease"},{"id":"T95","span":{"begin":2135,"end":2138},"obj":"Disease"},{"id":"T97","span":{"begin":2537,"end":2545},"obj":"Disease"},{"id":"T98","span":{"begin":2574,"end":2583},"obj":"Disease"}],"attributes":[{"id":"A92","pred":"mondo_id","subj":"T92","obj":"http://purl.obolibrary.org/obo/MONDO_0005812"},{"id":"A93","pred":"mondo_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/MONDO_0008449"},{"id":"A94","pred":"mondo_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/MONDO_0018075"},{"id":"A95","pred":"mondo_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/MONDO_0008449"},{"id":"A96","pred":"mondo_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/MONDO_0018075"},{"id":"A97","pred":"mondo_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A98","pred":"mondo_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/MONDO_0002251"},{"subj":"T92","pred":"source","obj":"LitCovid-PD-MONDO"},{"subj":"T93","pred":"source","obj":"LitCovid-PD-MONDO"},{"subj":"T95","pred":"source","obj":"LitCovid-PD-MONDO"},{"subj":"T97","pred":"source","obj":"LitCovid-PD-MONDO"},{"subj":"T98","pred":"source","obj":"LitCovid-PD-MONDO"}]},{"project":"LitCovid-PD-CLO","denotations":[{"id":"T181","span":{"begin":82,"end":85},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T182","span":{"begin":103,"end":104},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T183","span":{"begin":299,"end":301},"obj":"http://purl.obolibrary.org/obo/CLO_0001000"},{"id":"T184","span":{"begin":512,"end":513},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T185","span":{"begin":649,"end":653},"obj":"http://purl.obolibrary.org/obo/CLO_0001627"},{"id":"T186","span":{"begin":682,"end":685},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T187","span":{"begin":775,"end":778},"obj":"http://purl.obolibrary.org/obo/CLO_0050884"},{"id":"T188","span":{"begin":827,"end":828},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T189","span":{"begin":858,"end":860},"obj":"http://purl.obolibrary.org/obo/CLO_0053794"},{"id":"T190","span":{"begin":939,"end":940},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T191","span":{"begin":1196,"end":1204},"obj":"http://purl.obolibrary.org/obo/CLO_0009985"},{"id":"T192","span":{"begin":1367,"end":1368},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T193","span":{"begin":1439,"end":1440},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T194","span":{"begin":1483,"end":1491},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T195","span":{"begin":1878,"end":1881},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T196","span":{"begin":1991,"end":1992},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T197","span":{"begin":2484,"end":2492},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T198","span":{"begin":2501,"end":2502},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T199","span":{"begin":2555,"end":2561},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T200","span":{"begin":2568,"end":2573},"obj":"http://purl.obolibrary.org/obo/CLO_0007836"},{"id":"T201","span":{"begin":2584,"end":2589},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T202","span":{"begin":2609,"end":2610},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T203","span":{"begin":2697,"end":2699},"obj":"http://purl.obolibrary.org/obo/CLO_0008933"},{"id":"T204","span":{"begin":3319,"end":3321},"obj":"http://purl.obolibrary.org/obo/CLO_0007874"},{"id":"T205","span":{"begin":3322,"end":3324},"obj":"http://purl.obolibrary.org/obo/CLO_0053799"},{"id":"T206","span":{"begin":3938,"end":3944},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"}],"attributes":[{"subj":"T181","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T182","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T183","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T184","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T185","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T186","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T187","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T188","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T189","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T190","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T191","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T192","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T193","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T194","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T195","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T196","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T197","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T198","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T199","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T200","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T201","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T202","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T203","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T204","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T205","pred":"source","obj":"LitCovid-PD-CLO"},{"subj":"T206","pred":"source","obj":"LitCovid-PD-CLO"}]},{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T200","span":{"begin":44,"end":53},"obj":"Chemical"},{"id":"T201","span":{"begin":67,"end":70},"obj":"Chemical"},{"id":"T203","span":{"begin":229,"end":232},"obj":"Chemical"},{"id":"T205","span":{"begin":393,"end":396},"obj":"Chemical"},{"id":"T207","span":{"begin":596,"end":605},"obj":"Chemical"},{"id":"T208","span":{"begin":671,"end":680},"obj":"Chemical"},{"id":"T209","span":{"begin":745,"end":761},"obj":"Chemical"},{"id":"T210","span":{"begin":968,"end":975},"obj":"Chemical"},{"id":"T211","span":{"begin":976,"end":983},"obj":"Chemical"},{"id":"T212","span":{"begin":988,"end":995},"obj":"Chemical"},{"id":"T213","span":{"begin":996,"end":1002},"obj":"Chemical"},{"id":"T214","span":{"begin":1265,"end":1271},"obj":"Chemical"},{"id":"T215","span":{"begin":1296,"end":1304},"obj":"Chemical"},{"id":"T216","span":{"begin":1506,"end":1513},"obj":"Chemical"},{"id":"T217","span":{"begin":1660,"end":1667},"obj":"Chemical"},{"id":"T218","span":{"begin":1969,"end":1977},"obj":"Chemical"},{"id":"T219","span":{"begin":1997,"end":2001},"obj":"Chemical"},{"id":"T220","span":{"begin":2070,"end":2081},"obj":"Chemical"},{"id":"T221","span":{"begin":2070,"end":2075},"obj":"Chemical"},{"id":"T222","span":{"begin":2076,"end":2081},"obj":"Chemical"},{"id":"T223","span":{"begin":2384,"end":2386},"obj":"Chemical"},{"id":"T224","span":{"begin":2697,"end":2699},"obj":"Chemical"},{"id":"T225","span":{"begin":2877,"end":2880},"obj":"Chemical"},{"id":"T227","span":{"begin":3104,"end":3111},"obj":"Chemical"},{"id":"T228","span":{"begin":3291,"end":3299},"obj":"Chemical"},{"id":"T229","span":{"begin":3300,"end":3309},"obj":"Chemical"},{"id":"T230","span":{"begin":3319,"end":3321},"obj":"Chemical"},{"id":"T231","span":{"begin":3602,"end":3610},"obj":"Chemical"},{"id":"T232","span":{"begin":3656,"end":3663},"obj":"Chemical"},{"id":"T233","span":{"begin":3749,"end":3757},"obj":"Chemical"},{"id":"T234","span":{"begin":3960,"end":3964},"obj":"Chemical"},{"id":"T235","span":{"begin":4025,"end":4039},"obj":"Chemical"}],"attributes":[{"id":"A200","pred":"chebi_id","subj":"T200","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A201","pred":"chebi_id","subj":"T201","obj":"http://purl.obolibrary.org/obo/CHEBI_53266"},{"id":"A202","pred":"chebi_id","subj":"T201","obj":"http://purl.obolibrary.org/obo/CHEBI_60614"},{"id":"A203","pred":"chebi_id","subj":"T203","obj":"http://purl.obolibrary.org/obo/CHEBI_53266"},{"id":"A204","pred":"chebi_id","subj":"T203","obj":"http://purl.obolibrary.org/obo/CHEBI_60614"},{"id":"A205","pred":"chebi_id","subj":"T205","obj":"http://purl.obolibrary.org/obo/CHEBI_53266"},{"id":"A206","pred":"chebi_id","subj":"T205","obj":"http://purl.obolibrary.org/obo/CHEBI_60614"},{"id":"A207","pred":"chebi_id","subj":"T207","obj":"http://purl.obolibrary.org/obo/CHEBI_132554"},{"id":"A208","pred":"chebi_id","subj":"T208","obj":"http://purl.obolibrary.org/obo/CHEBI_25106"},{"id":"A209","pred":"chebi_id","subj":"T209","obj":"http://purl.obolibrary.org/obo/CHEBI_35610"},{"id":"A210","pred":"chebi_id","subj":"T210","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A211","pred":"chebi_id","subj":"T211","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A212","pred":"chebi_id","subj":"T212","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A213","pred":"chebi_id","subj":"T213","obj":"http://purl.obolibrary.org/obo/CHEBI_52214"},{"id":"A214","pred":"chebi_id","subj":"T214","obj":"http://purl.obolibrary.org/obo/CHEBI_52214"},{"id":"A215","pred":"chebi_id","subj":"T215","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A216","pred":"chebi_id","subj":"T216","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A217","pred":"chebi_id","subj":"T217","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A218","pred":"chebi_id","subj":"T218","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A219","pred":"chebi_id","subj":"T219","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A220","pred":"chebi_id","subj":"T220","obj":"http://purl.obolibrary.org/obo/CHEBI_33709"},{"id":"A221","pred":"chebi_id","subj":"T221","obj":"http://purl.obolibrary.org/obo/CHEBI_46882"},{"id":"A222","pred":"chebi_id","subj":"T222","obj":"http://purl.obolibrary.org/obo/CHEBI_37527"},{"id":"A223","pred":"chebi_id","subj":"T223","obj":"http://purl.obolibrary.org/obo/CHEBI_29401"},{"id":"A224","pred":"chebi_id","subj":"T224","obj":"http://purl.obolibrary.org/obo/CHEBI_29386"},{"id":"A225","pred":"chebi_id","subj":"T225","obj":"http://purl.obolibrary.org/obo/CHEBI_53266"},{"id":"A226","pred":"chebi_id","subj":"T225","obj":"http://purl.obolibrary.org/obo/CHEBI_60614"},{"id":"A227","pred":"chebi_id","subj":"T227","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A228","pred":"chebi_id","subj":"T228","obj":"http://purl.obolibrary.org/obo/CHEBI_49637"},{"id":"A229","pred":"chebi_id","subj":"T229","obj":"http://purl.obolibrary.org/obo/CHEBI_29237"},{"id":"A230","pred":"chebi_id","subj":"T230","obj":"http://purl.obolibrary.org/obo/CHEBI_73613"},{"id":"A231","pred":"chebi_id","subj":"T231","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A232","pred":"chebi_id","subj":"T232","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A233","pred":"chebi_id","subj":"T233","obj":"http://purl.obolibrary.org/obo/CHEBI_25367"},{"id":"A234","pred":"chebi_id","subj":"T234","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A235","pred":"chebi_id","subj":"T235","obj":"http://purl.obolibrary.org/obo/CHEBI_33585"},{"subj":"T200","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T201","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T203","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T205","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T207","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T208","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T209","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T210","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T211","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T212","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T213","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T214","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T215","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T216","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T217","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T218","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T219","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T220","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T221","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T222","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T223","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T224","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T225","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T227","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T228","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T229","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T230","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T231","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T232","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T233","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T234","pred":"source","obj":"LitCovid-PD-CHEBI"},{"subj":"T235","pred":"source","obj":"LitCovid-PD-CHEBI"}]},{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T19","span":{"begin":1710,"end":1718},"obj":"http://purl.obolibrary.org/obo/GO_0007610"},{"id":"T20","span":{"begin":1771,"end":1780},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T21","span":{"begin":2794,"end":2803},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T22","span":{"begin":3310,"end":3318},"obj":"http://purl.obolibrary.org/obo/GO_0015297"}],"attributes":[{"subj":"T19","pred":"source","obj":"LitCovid-PD-GO-BP"},{"subj":"T20","pred":"source","obj":"LitCovid-PD-GO-BP"},{"subj":"T21","pred":"source","obj":"LitCovid-PD-GO-BP"},{"subj":"T22","pred":"source","obj":"LitCovid-PD-GO-BP"}]},{"project":"LitCovid-PD-HP","denotations":[{"id":"T4","span":{"begin":2574,"end":2583},"obj":"Phenotype"}],"attributes":[{"id":"A4","pred":"hp_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/HP_0012115"},{"subj":"T4","pred":"source","obj":"LitCovid-PD-HP"}]},{"project":"LitCovid-sentences","denotations":[{"id":"T193","span":{"begin":0,"end":26},"obj":"Sentence"},{"id":"T194","span":{"begin":27,"end":161},"obj":"Sentence"},{"id":"T195","span":{"begin":162,"end":1153},"obj":"Sentence"},{"id":"T196","span":{"begin":1154,"end":1385},"obj":"Sentence"},{"id":"T197","span":{"begin":1386,"end":1589},"obj":"Sentence"},{"id":"T198","span":{"begin":1590,"end":1781},"obj":"Sentence"},{"id":"T199","span":{"begin":1782,"end":1925},"obj":"Sentence"},{"id":"T200","span":{"begin":1926,"end":2027},"obj":"Sentence"},{"id":"T201","span":{"begin":2028,"end":2164},"obj":"Sentence"},{"id":"T202","span":{"begin":2165,"end":2388},"obj":"Sentence"},{"id":"T203","span":{"begin":2389,"end":2546},"obj":"Sentence"},{"id":"T204","span":{"begin":2547,"end":2701},"obj":"Sentence"},{"id":"T205","span":{"begin":2702,"end":2780},"obj":"Sentence"},{"id":"T206","span":{"begin":2781,"end":2952},"obj":"Sentence"},{"id":"T207","span":{"begin":2953,"end":3066},"obj":"Sentence"},{"id":"T208","span":{"begin":3067,"end":3189},"obj":"Sentence"},{"id":"T209","span":{"begin":3190,"end":3516},"obj":"Sentence"},{"id":"T210","span":{"begin":3517,"end":3634},"obj":"Sentence"},{"id":"T211","span":{"begin":3635,"end":3785},"obj":"Sentence"},{"id":"T212","span":{"begin":3786,"end":3898},"obj":"Sentence"},{"id":"T213","span":{"begin":3899,"end":4066},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"T193","pred":"source","obj":"LitCovid-sentences"},{"subj":"T194","pred":"source","obj":"LitCovid-sentences"},{"subj":"T195","pred":"source","obj":"LitCovid-sentences"},{"subj":"T196","pred":"source","obj":"LitCovid-sentences"},{"subj":"T197","pred":"source","obj":"LitCovid-sentences"},{"subj":"T198","pred":"source","obj":"LitCovid-sentences"},{"subj":"T199","pred":"source","obj":"LitCovid-sentences"},{"subj":"T200","pred":"source","obj":"LitCovid-sentences"},{"subj":"T201","pred":"source","obj":"LitCovid-sentences"},{"subj":"T202","pred":"source","obj":"LitCovid-sentences"},{"subj":"T203","pred":"source","obj":"LitCovid-sentences"},{"subj":"T204","pred":"source","obj":"LitCovid-sentences"},{"subj":"T205","pred":"source","obj":"LitCovid-sentences"},{"subj":"T206","pred":"source","obj":"LitCovid-sentences"},{"subj":"T207","pred":"source","obj":"LitCovid-sentences"},{"subj":"T208","pred":"source","obj":"LitCovid-sentences"},{"subj":"T209","pred":"source","obj":"LitCovid-sentences"},{"subj":"T210","pred":"source","obj":"LitCovid-sentences"},{"subj":"T211","pred":"source","obj":"LitCovid-sentences"},{"subj":"T212","pred":"source","obj":"LitCovid-sentences"},{"subj":"T213","pred":"source","obj":"LitCovid-sentences"}]},{"project":"LitCovid-PubTator","denotations":[{"id":"418","span":{"begin":1767,"end":1770},"obj":"Gene"},{"id":"419","span":{"begin":1562,"end":1570},"obj":"Species"},{"id":"420","span":{"begin":1613,"end":1621},"obj":"Species"},{"id":"421","span":{"begin":2032,"end":2047},"obj":"Species"},{"id":"422","span":{"begin":2056,"end":2064},"obj":"Species"},{"id":"423","span":{"begin":2248,"end":2263},"obj":"Species"},{"id":"424","span":{"begin":2568,"end":2589},"obj":"Species"},{"id":"425","span":{"begin":452,"end":461},"obj":"Species"},{"id":"426","span":{"begin":2591,"end":2594},"obj":"Species"},{"id":"427","span":{"begin":2673,"end":2676},"obj":"Species"},{"id":"428","span":{"begin":471,"end":480},"obj":"Chemical"},{"id":"429","span":{"begin":664,"end":680},"obj":"Chemical"},{"id":"430","span":{"begin":1722,"end":1727},"obj":"Chemical"},{"id":"431","span":{"begin":2133,"end":2138},"obj":"Chemical"},{"id":"432","span":{"begin":3291,"end":3299},"obj":"Chemical"},{"id":"433","span":{"begin":3300,"end":3309},"obj":"Chemical"},{"id":"434","span":{"begin":1649,"end":1679},"obj":"Disease"},{"id":"435","span":{"begin":2537,"end":2545},"obj":"Disease"},{"id":"437","span":{"begin":3645,"end":3653},"obj":"Species"}],"attributes":[{"id":"A418","pred":"tao:has_database_id","subj":"418","obj":"Gene:55599"},{"id":"A419","pred":"tao:has_database_id","subj":"419","obj":"Tax:1335626"},{"id":"A420","pred":"tao:has_database_id","subj":"420","obj":"Tax:1335626"},{"id":"A421","pred":"tao:has_database_id","subj":"421","obj":"Tax:694002"},{"id":"A422","pred":"tao:has_database_id","subj":"422","obj":"Tax:1335626"},{"id":"A423","pred":"tao:has_database_id","subj":"423","obj":"Tax:694002"},{"id":"A424","pred":"tao:has_database_id","subj":"424","obj":"Tax:11138"},{"id":"A425","pred":"tao:has_database_id","subj":"425","obj":"Tax:11309"},{"id":"A426","pred":"tao:has_database_id","subj":"426","obj":"Tax:11138"},{"id":"A427","pred":"tao:has_database_id","subj":"427","obj":"Tax:11138"},{"id":"A432","pred":"tao:has_database_id","subj":"432","obj":"MESH:D006859"},{"id":"A433","pred":"tao:has_database_id","subj":"433","obj":"MESH:D003903"},{"id":"A434","pred":"tao:has_database_id","subj":"434","obj":"MESH:D001791"},{"id":"A435","pred":"tao:has_database_id","subj":"435","obj":"MESH:C000657245"},{"id":"A437","pred":"tao:has_database_id","subj":"437","obj":"Tax:1335626"},{"subj":"418","pred":"source","obj":"LitCovid-PubTator"},{"subj":"419","pred":"source","obj":"LitCovid-PubTator"},{"subj":"420","pred":"source","obj":"LitCovid-PubTator"},{"subj":"421","pred":"source","obj":"LitCovid-PubTator"},{"subj":"422","pred":"source","obj":"LitCovid-PubTator"},{"subj":"423","pred":"source","obj":"LitCovid-PubTator"},{"subj":"424","pred":"source","obj":"LitCovid-PubTator"},{"subj":"425","pred":"source","obj":"LitCovid-PubTator"},{"subj":"426","pred":"source","obj":"LitCovid-PubTator"},{"subj":"427","pred":"source","obj":"LitCovid-PubTator"},{"subj":"428","pred":"source","obj":"LitCovid-PubTator"},{"subj":"429","pred":"source","obj":"LitCovid-PubTator"},{"subj":"430","pred":"source","obj":"LitCovid-PubTator"},{"subj":"431","pred":"source","obj":"LitCovid-PubTator"},{"subj":"432","pred":"source","obj":"LitCovid-PubTator"},{"subj":"433","pred":"source","obj":"LitCovid-PubTator"},{"subj":"434","pred":"source","obj":"LitCovid-PubTator"},{"subj":"435","pred":"source","obj":"LitCovid-PubTator"},{"subj":"437","pred":"source","obj":"LitCovid-PubTator"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}]},{"project":"2_test","denotations":[{"id":"32105468-31141413-61929515","span":{"begin":299,"end":301},"obj":"31141413"},{"id":"32105468-28300404-61929516","span":{"begin":302,"end":304},"obj":"28300404"},{"id":"32105468-27820802-61929517","span":{"begin":440,"end":442},"obj":"27820802"},{"id":"32105468-20512121-61929518","span":{"begin":635,"end":637},"obj":"20512121"},{"id":"32105468-15797212-61929519","span":{"begin":858,"end":860},"obj":"15797212"},{"id":"32105468-7876075-61929520","span":{"begin":861,"end":863},"obj":"7876075"},{"id":"32105468-29308120-61929521","span":{"begin":1016,"end":1018},"obj":"29308120"},{"id":"32105468-16775348-61929522","span":{"begin":2267,"end":2269},"obj":"16775348"},{"id":"32105468-16503614-61929523","span":{"begin":3322,"end":3324},"obj":"16503614"}],"attributes":[{"subj":"32105468-31141413-61929515","pred":"source","obj":"2_test"},{"subj":"32105468-28300404-61929516","pred":"source","obj":"2_test"},{"subj":"32105468-27820802-61929517","pred":"source","obj":"2_test"},{"subj":"32105468-20512121-61929518","pred":"source","obj":"2_test"},{"subj":"32105468-15797212-61929519","pred":"source","obj":"2_test"},{"subj":"32105468-7876075-61929520","pred":"source","obj":"2_test"},{"subj":"32105468-29308120-61929521","pred":"source","obj":"2_test"},{"subj":"32105468-16775348-61929522","pred":"source","obj":"2_test"},{"subj":"32105468-16503614-61929523","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"LitCovid-PMC-OGER-BB","color":"#c8ec93","default":true},{"id":"LitCovid-PD-FMA-UBERON","color":"#ec93e2"},{"id":"LitCovid-PD-UBERON","color":"#93ecdc"},{"id":"LitCovid_AGAC","color":"#ecc293"},{"id":"LitCovid-PD-MONDO","color":"#a893ec"},{"id":"LitCovid-PD-CLO","color":"#98ec93"},{"id":"LitCovid-PD-CHEBI","color":"#ec93b2"},{"id":"LitCovid-PD-GO-BP","color":"#93ccec"},{"id":"LitCovid-PD-HP","color":"#e6ec93"},{"id":"LitCovid-sentences","color":"#d893ec"},{"id":"LitCovid-PubTator","color":"#93ecbe"},{"id":"2_test","color":"#eca493"}]}]}}