Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold
Identifieur interne : 000011 ( Istex/Checkpoint ); précédent : 000010; suivant : 000012Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold
Auteurs : Kenta Teruya [Japon] ; Yasunao Hattori [Japon] ; Yasuhiro Shimamoto [Japon] ; Kazuya Kobayashi [Japon] ; Akira Sanjoh [Japon] ; Atsushi Nakagawa [Japon] ; Eiki Yamashita [Japon] ; Kenichi Akaji [Japon]Source :
- Peptide Science [ 0006-3525 ] ; 2016-07.
Abstract
Design of inhibitors against severe acute respiratory syndrome (SARS) chymotrypsin‐like protease (3CLpro) is a potentially important approach to fight against SARS. We have developed several synthetic inhibitors by structure‐based drug design. In this report, we reveal two crystal structures of SARS 3CLpro complexed with two new inhibitors based on our previous work. These structures combined with six crystal structures complexed with a series of related ligands reported by us are collectively analyzed. To these eight complexes, the structural basis for inhibitor binding was analyzed by the COMBINE method, which is a chemometrical analysis optimized for the protein–ligand complex. The analysis revealed that the first two latent variables gave a cumulative contribution ratio of r2 = 0.971. Interestingly, scores using the second latent variables for each complex were strongly correlated with root mean square deviations (RMSDs) of side‐chain heavy atoms of Met49 from those of the intact crystal structure of SARS‐3CLpro (r = 0.77) enlarging the S2 pocket. The substantial contribution of this side chain (∼10%) for the explanation of pIC50s was dependent on stereochemistry and the chemical structure of the ligand adapted to the S2 pocket of the protease. Thus, starting from a substrate mimic inhibitor, a design for a central scaffold for a low molecular weight inhibitor was evaluated to develop a further potent inhibitor. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 391–403, 2016.
Url:
DOI: 10.1002/bip.22773
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
ISTEX:EE5073C3B56351C6A69636DB1D0F458DCEC34117Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold</title><author><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name></author><author><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name></author><author><name sortKey="Shimamoto, Yasuhiro" sort="Shimamoto, Yasuhiro" uniqKey="Shimamoto Y" first="Yasuhiro" last="Shimamoto">Yasuhiro Shimamoto</name></author><author><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name></author><author><name sortKey="Sanjoh, Akira" sort="Sanjoh, Akira" uniqKey="Sanjoh A" first="Akira" last="Sanjoh">Akira Sanjoh</name></author><author><name sortKey="Nakagawa, Atsushi" sort="Nakagawa, Atsushi" uniqKey="Nakagawa A" first="Atsushi" last="Nakagawa">Atsushi Nakagawa</name></author><author><name sortKey="Yamashita, Eiki" sort="Yamashita, Eiki" uniqKey="Yamashita E" first="Eiki" last="Yamashita">Eiki Yamashita</name></author><author><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:EE5073C3B56351C6A69636DB1D0F458DCEC34117</idno><date when="2016" year="2016">2016</date><idno type="doi">10.1002/bip.22773</idno><idno type="url">https://api.istex.fr/ark:/67375/WNG-5DWGNLVL-6/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000A90</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000A90</idno><idno type="wicri:Area/Istex/Curation">000A90</idno><idno type="wicri:Area/Istex/Checkpoint">000011</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000011</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold</title><author><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurochemistry, Tohoku University Graduate School of Medicine, 980‐8575, Aoba‐Ku Sendai</wicri:regionArea><wicri:noRegion>Aoba‐Ku Sendai</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Japon</country></affiliation></author><author><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto, 607‐8412, Yamashina‐Ku</wicri:regionArea><wicri:noRegion>Yamashina‐Ku</wicri:noRegion></affiliation></author><author><name sortKey="Shimamoto, Yasuhiro" sort="Shimamoto, Yasuhiro" uniqKey="Shimamoto Y" first="Yasuhiro" last="Shimamoto">Yasuhiro Shimamoto</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto, 607‐8412, Yamashina‐Ku</wicri:regionArea><wicri:noRegion>Yamashina‐Ku</wicri:noRegion></affiliation></author><author><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto, 607‐8412, Yamashina‐Ku</wicri:regionArea><wicri:noRegion>Yamashina‐Ku</wicri:noRegion></affiliation></author><author><name sortKey="Sanjoh, Akira" sort="Sanjoh, Akira" uniqKey="Sanjoh A" first="Akira" last="Sanjoh">Akira Sanjoh</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>R&D Center, Protein Wave Co, 631‐0006, Nara</wicri:regionArea><wicri:noRegion>Nara</wicri:noRegion></affiliation></author><author><name sortKey="Nakagawa, Atsushi" sort="Nakagawa, Atsushi" uniqKey="Nakagawa A" first="Atsushi" last="Nakagawa">Atsushi Nakagawa</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Institute for Protein Research, Osaka University, Osaka, 565‐0871, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Yamashita, Eiki" sort="Yamashita, Eiki" uniqKey="Yamashita E" first="Eiki" last="Yamashita">Eiki Yamashita</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Institute for Protein Research, Osaka University, Osaka, 565‐0871, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto, 607‐8412, Yamashina‐Ku</wicri:regionArea><wicri:noRegion>Yamashina‐Ku</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Japon</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Peptide Science</title><title level="j" type="sub">Emerging Peptide Science from Japan</title><title level="j" type="alt">PEPTIDE SCIENCE</title><idno type="ISSN">0006-3525</idno><idno type="eISSN">1097-0282</idno><imprint><biblScope unit="vol">106</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="391">391</biblScope><biblScope unit="page" to="403">403</biblScope><biblScope unit="page-count">13</biblScope><date type="published" when="2016-07">2016-07</date></imprint><idno type="ISSN">0006-3525</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-3525</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Design of inhibitors against severe acute respiratory syndrome (SARS) chymotrypsin‐like protease (3CLpro) is a potentially important approach to fight against SARS. We have developed several synthetic inhibitors by structure‐based drug design. In this report, we reveal two crystal structures of SARS 3CLpro complexed with two new inhibitors based on our previous work. These structures combined with six crystal structures complexed with a series of related ligands reported by us are collectively analyzed. To these eight complexes, the structural basis for inhibitor binding was analyzed by the COMBINE method, which is a chemometrical analysis optimized for the protein–ligand complex. The analysis revealed that the first two latent variables gave a cumulative contribution ratio of r2 = 0.971. Interestingly, scores using the second latent variables for each complex were strongly correlated with root mean square deviations (RMSDs) of side‐chain heavy atoms of Met49 from those of the intact crystal structure of SARS‐3CLpro (r = 0.77) enlarging the S2 pocket. The substantial contribution of this side chain (∼10%) for the explanation of pIC50s was dependent on stereochemistry and the chemical structure of the ligand adapted to the S2 pocket of the protease. Thus, starting from a substrate mimic inhibitor, a design for a central scaffold for a low molecular weight inhibitor was evaluated to develop a further potent inhibitor. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 391–403, 2016.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name></noRegion><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name><name sortKey="Nakagawa, Atsushi" sort="Nakagawa, Atsushi" uniqKey="Nakagawa A" first="Atsushi" last="Nakagawa">Atsushi Nakagawa</name><name sortKey="Sanjoh, Akira" sort="Sanjoh, Akira" uniqKey="Sanjoh A" first="Akira" last="Sanjoh">Akira Sanjoh</name><name sortKey="Shimamoto, Yasuhiro" sort="Shimamoto, Yasuhiro" uniqKey="Shimamoto Y" first="Yasuhiro" last="Shimamoto">Yasuhiro Shimamoto</name><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name><name sortKey="Yamashita, Eiki" sort="Yamashita, Eiki" uniqKey="Yamashita E" first="Eiki" last="Yamashita">Eiki Yamashita</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Istex/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000011 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Checkpoint/biblio.hfd -nk 000011 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Istex
|étape= Checkpoint
|type= RBID
|clé= ISTEX:EE5073C3B56351C6A69636DB1D0F458DCEC34117
|texte= Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold
}}
| This area was generated with Dilib version V0.6.33. |  |