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Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since...

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Autores principales: Szilágyi, Katalin, Hajdú, István, Flachner, Beáta, Lőrincz, Zsolt, Balczer, Júlia, Gál, Péter, Závodszky, Péter, Pirli, Chiara, Balogh, Balázs, Mándity, István M., Cseh, Sándor, Dormán, György
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832932/
https://www.ncbi.nlm.nih.gov/pubmed/31600984
http://dx.doi.org/10.3390/molecules24203641
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author Szilágyi, Katalin
Hajdú, István
Flachner, Beáta
Lőrincz, Zsolt
Balczer, Júlia
Gál, Péter
Závodszky, Péter
Pirli, Chiara
Balogh, Balázs
Mándity, István M.
Cseh, Sándor
Dormán, György
author_facet Szilágyi, Katalin
Hajdú, István
Flachner, Beáta
Lőrincz, Zsolt
Balczer, Júlia
Gál, Péter
Závodszky, Péter
Pirli, Chiara
Balogh, Balázs
Mándity, István M.
Cseh, Sándor
Dormán, György
author_sort Szilágyi, Katalin
collection PubMed
description The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.
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spelling pubmed-68329322019-11-25 Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches Szilágyi, Katalin Hajdú, István Flachner, Beáta Lőrincz, Zsolt Balczer, Júlia Gál, Péter Závodszky, Péter Pirli, Chiara Balogh, Balázs Mándity, István M. Cseh, Sándor Dormán, György Molecules Article The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively. MDPI 2019-10-09 /pmc/articles/PMC6832932/ /pubmed/31600984 http://dx.doi.org/10.3390/molecules24203641 Text en © 2019 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/).
spellingShingle Article
Szilágyi, Katalin
Hajdú, István
Flachner, Beáta
Lőrincz, Zsolt
Balczer, Júlia
Gál, Péter
Závodszky, Péter
Pirli, Chiara
Balogh, Balázs
Mándity, István M.
Cseh, Sándor
Dormán, György
Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title_full Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title_fullStr Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title_full_unstemmed Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title_short Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
title_sort design and selection of novel c1s inhibitors by in silico and in vitro approaches
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832932/
https://www.ncbi.nlm.nih.gov/pubmed/31600984
http://dx.doi.org/10.3390/molecules24203641
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