PMC:7571312 / 6194-8004 JSON TXT

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LitCovid-PD-FMA-UBERON

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T55817","span":{"begin":1391,"end":1400},"obj":"Body_part"},{"id":"T4591","span":{"begin":1593,"end":1601},"obj":"Body_part"},{"id":"T6474","span":{"begin":1718,"end":1725},"obj":"Body_part"},{"id":"T1473","span":{"begin":1726,"end":1734},"obj":"Body_part"}],"attributes":[{"id":"A46770","pred":"fma_id","subj":"T55817","obj":"http://purl.org/sig/ont/fma/fma82752"},{"id":"A36909","pred":"fma_id","subj":"T4591","obj":"http://purl.org/sig/ont/fma/fma13478"},{"id":"A21519","pred":"fma_id","subj":"T6474","obj":"http://purl.org/sig/ont/fma/fma67257"},{"id":"A47184","pred":"fma_id","subj":"T1473","obj":"http://purl.org/sig/ont/fma/fma13478"}],"text":"Performing a similar analysis, we tested 1 and additional HRV 3Cpro inhibitors that displayed very weak to unmeasurable SARS CoV-1 3CLpro inhibition. Concurrently, new Michael acceptor derivatives were designed that tested P1/P2 alterations and truncation of the P3/P4 binding motif to optimize SARS CoV-1 3CLpro inhibition. Compound 2, a derivative that contains an indole capping group at P2, displayed modest levels of irreversible inhibition (kobs/I = 586 ± 11 M–1 s–1) that enabled cocrystallization in complex with SARS CoV-1 3CLpro (PDB code 6XHO).29 Comparison of this structure with the complex of 1 in HRV 3Cpro helped to rationalize the poor performance of the warhead, which had been successful in HRV. The structure of the SARS CoV-1 3CLpro complex revealed an eclipsed torsion about the resulting sp3 α,β-carbons from the Michael acceptor (Figure 3). Furthermore, the carbonyl oxygen sp2 lone pair electrons are not aligned well with either 3CLpro hydrogen bond donor of the oxyanion hole. Specifically, the hydrogen bond between the carbonyl oxygen and the Gly143 NH in the SARS CoV-1 3CLpro complex is 3.4 Å, while the corresponding hydrogen bond distance is a much more favorable 2.8 Å in the complex of 1 with HRV 3Cpro. In contrast to these unfavorable interactions, the constrained lactam30 at the P1 site, which was designed to be isosteric with the highly conserved P1 glutamine present in all SARS CoV substrates, is well positioned in the S1 pocket making a favorable hydrogen bond to His163. The NH of the lactam is within the hydrogen bond distance to Glu166 and the backbone oxygen of Phe140 in the 3CLpro. Additionally, the NH of the indole P2 capping moiety makes a hydrogen bond with the protein backbone while it extends across an otherwise lipophilic surface over the P3 pocket."}

LitCovid-PD-MONDO

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T34","span":{"begin":120,"end":124},"obj":"Disease"},{"id":"T35","span":{"begin":295,"end":299},"obj":"Disease"},{"id":"T36","span":{"begin":521,"end":525},"obj":"Disease"},{"id":"T37","span":{"begin":736,"end":740},"obj":"Disease"},{"id":"T38","span":{"begin":1089,"end":1093},"obj":"Disease"},{"id":"T39","span":{"begin":1416,"end":1420},"obj":"Disease"}],"attributes":[{"id":"A34","pred":"mondo_id","subj":"T34","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A35","pred":"mondo_id","subj":"T35","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A36","pred":"mondo_id","subj":"T36","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A37","pred":"mondo_id","subj":"T37","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A38","pred":"mondo_id","subj":"T38","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A39","pred":"mondo_id","subj":"T39","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"}],"text":"Performing a similar analysis, we tested 1 and additional HRV 3Cpro inhibitors that displayed very weak to unmeasurable SARS CoV-1 3CLpro inhibition. Concurrently, new Michael acceptor derivatives were designed that tested P1/P2 alterations and truncation of the P3/P4 binding motif to optimize SARS CoV-1 3CLpro inhibition. Compound 2, a derivative that contains an indole capping group at P2, displayed modest levels of irreversible inhibition (kobs/I = 586 ± 11 M–1 s–1) that enabled cocrystallization in complex with SARS CoV-1 3CLpro (PDB code 6XHO).29 Comparison of this structure with the complex of 1 in HRV 3Cpro helped to rationalize the poor performance of the warhead, which had been successful in HRV. The structure of the SARS CoV-1 3CLpro complex revealed an eclipsed torsion about the resulting sp3 α,β-carbons from the Michael acceptor (Figure 3). Furthermore, the carbonyl oxygen sp2 lone pair electrons are not aligned well with either 3CLpro hydrogen bond donor of the oxyanion hole. Specifically, the hydrogen bond between the carbonyl oxygen and the Gly143 NH in the SARS CoV-1 3CLpro complex is 3.4 Å, while the corresponding hydrogen bond distance is a much more favorable 2.8 Å in the complex of 1 with HRV 3Cpro. In contrast to these unfavorable interactions, the constrained lactam30 at the P1 site, which was designed to be isosteric with the highly conserved P1 glutamine present in all SARS CoV substrates, is well positioned in the S1 pocket making a favorable hydrogen bond to His163. The NH of the lactam is within the hydrogen bond distance to Glu166 and the backbone oxygen of Phe140 in the 3CLpro. Additionally, the NH of the indole P2 capping moiety makes a hydrogen bond with the protein backbone while it extends across an otherwise lipophilic surface over the P3 pocket."}

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T28","span":{"begin":0,"end":149},"obj":"Sentence"},{"id":"T29","span":{"begin":150,"end":324},"obj":"Sentence"},{"id":"T30","span":{"begin":325,"end":714},"obj":"Sentence"},{"id":"T31","span":{"begin":715,"end":864},"obj":"Sentence"},{"id":"T32","span":{"begin":865,"end":1003},"obj":"Sentence"},{"id":"T33","span":{"begin":1004,"end":1238},"obj":"Sentence"},{"id":"T34","span":{"begin":1239,"end":1516},"obj":"Sentence"},{"id":"T35","span":{"begin":1517,"end":1633},"obj":"Sentence"},{"id":"T36","span":{"begin":1634,"end":1810},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Performing a similar analysis, we tested 1 and additional HRV 3Cpro inhibitors that displayed very weak to unmeasurable SARS CoV-1 3CLpro inhibition. Concurrently, new Michael acceptor derivatives were designed that tested P1/P2 alterations and truncation of the P3/P4 binding motif to optimize SARS CoV-1 3CLpro inhibition. Compound 2, a derivative that contains an indole capping group at P2, displayed modest levels of irreversible inhibition (kobs/I = 586 ± 11 M–1 s–1) that enabled cocrystallization in complex with SARS CoV-1 3CLpro (PDB code 6XHO).29 Comparison of this structure with the complex of 1 in HRV 3Cpro helped to rationalize the poor performance of the warhead, which had been successful in HRV. The structure of the SARS CoV-1 3CLpro complex revealed an eclipsed torsion about the resulting sp3 α,β-carbons from the Michael acceptor (Figure 3). Furthermore, the carbonyl oxygen sp2 lone pair electrons are not aligned well with either 3CLpro hydrogen bond donor of the oxyanion hole. Specifically, the hydrogen bond between the carbonyl oxygen and the Gly143 NH in the SARS CoV-1 3CLpro complex is 3.4 Å, while the corresponding hydrogen bond distance is a much more favorable 2.8 Å in the complex of 1 with HRV 3Cpro. In contrast to these unfavorable interactions, the constrained lactam30 at the P1 site, which was designed to be isosteric with the highly conserved P1 glutamine present in all SARS CoV substrates, is well positioned in the S1 pocket making a favorable hydrogen bond to His163. The NH of the lactam is within the hydrogen bond distance to Glu166 and the backbone oxygen of Phe140 in the 3CLpro. Additionally, the NH of the indole P2 capping moiety makes a hydrogen bond with the protein backbone while it extends across an otherwise lipophilic surface over the P3 pocket."}

LitCovid-PubTator

2_test

{"project":"2_test","denotations":[{"id":"33054210-10197965-61913454","span":{"begin":1308,"end":1310},"obj":"10197965"}],"text":"Performing a similar analysis, we tested 1 and additional HRV 3Cpro inhibitors that displayed very weak to unmeasurable SARS CoV-1 3CLpro inhibition. Concurrently, new Michael acceptor derivatives were designed that tested P1/P2 alterations and truncation of the P3/P4 binding motif to optimize SARS CoV-1 3CLpro inhibition. Compound 2, a derivative that contains an indole capping group at P2, displayed modest levels of irreversible inhibition (kobs/I = 586 ± 11 M–1 s–1) that enabled cocrystallization in complex with SARS CoV-1 3CLpro (PDB code 6XHO).29 Comparison of this structure with the complex of 1 in HRV 3Cpro helped to rationalize the poor performance of the warhead, which had been successful in HRV. The structure of the SARS CoV-1 3CLpro complex revealed an eclipsed torsion about the resulting sp3 α,β-carbons from the Michael acceptor (Figure 3). Furthermore, the carbonyl oxygen sp2 lone pair electrons are not aligned well with either 3CLpro hydrogen bond donor of the oxyanion hole. Specifically, the hydrogen bond between the carbonyl oxygen and the Gly143 NH in the SARS CoV-1 3CLpro complex is 3.4 Å, while the corresponding hydrogen bond distance is a much more favorable 2.8 Å in the complex of 1 with HRV 3Cpro. In contrast to these unfavorable interactions, the constrained lactam30 at the P1 site, which was designed to be isosteric with the highly conserved P1 glutamine present in all SARS CoV substrates, is well positioned in the S1 pocket making a favorable hydrogen bond to His163. The NH of the lactam is within the hydrogen bond distance to Glu166 and the backbone oxygen of Phe140 in the 3CLpro. Additionally, the NH of the indole P2 capping moiety makes a hydrogen bond with the protein backbone while it extends across an otherwise lipophilic surface over the P3 pocket."}