Design of MMP-1 inhibitors via SAR transfer and experimental validation

New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure–activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5–7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP...

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Autores principales: Umedera, Kohei, Yoshimori, Atsushi, Bajorath, Jürgen, Nakamura, Hiroyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9719525/
https://www.ncbi.nlm.nih.gov/pubmed/36463250
http://dx.doi.org/10.1038/s41598-022-25079-4
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author Umedera, Kohei
Yoshimori, Atsushi
Bajorath, Jürgen
Nakamura, Hiroyuki
author_facet Umedera, Kohei
Yoshimori, Atsushi
Bajorath, Jürgen
Nakamura, Hiroyuki
author_sort Umedera, Kohei
collection PubMed
description New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure–activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5–7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP-1 inhibitory activity. Among these, compound 6 having a Cl substituent at the R(1) site was found to possess ca. 3.5 times higher inhibitory activity against MMP-1 than the previously reported compound 4. The observed potency was consistent with the presence of an SAR transfer event between analogous MMP-1 and KIF11 inhibitors. Pharmacophore fitting revealed that the higher inhibitory activity of compound 6 compared to compound 4 against MMP-1 might be due to a halogen bond interaction between the Cl substituent of compound 6 and residue ARG214 of MMP-1.
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spelling pubmed-97195252022-12-05 Design of MMP-1 inhibitors via SAR transfer and experimental validation Umedera, Kohei Yoshimori, Atsushi Bajorath, Jürgen Nakamura, Hiroyuki Sci Rep Article New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure–activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5–7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP-1 inhibitory activity. Among these, compound 6 having a Cl substituent at the R(1) site was found to possess ca. 3.5 times higher inhibitory activity against MMP-1 than the previously reported compound 4. The observed potency was consistent with the presence of an SAR transfer event between analogous MMP-1 and KIF11 inhibitors. Pharmacophore fitting revealed that the higher inhibitory activity of compound 6 compared to compound 4 against MMP-1 might be due to a halogen bond interaction between the Cl substituent of compound 6 and residue ARG214 of MMP-1. Nature Publishing Group UK 2022-12-03 /pmc/articles/PMC9719525/ /pubmed/36463250 http://dx.doi.org/10.1038/s41598-022-25079-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Umedera, Kohei
Yoshimori, Atsushi
Bajorath, Jürgen
Nakamura, Hiroyuki
Design of MMP-1 inhibitors via SAR transfer and experimental validation
title Design of MMP-1 inhibitors via SAR transfer and experimental validation
title_full Design of MMP-1 inhibitors via SAR transfer and experimental validation
title_fullStr Design of MMP-1 inhibitors via SAR transfer and experimental validation
title_full_unstemmed Design of MMP-1 inhibitors via SAR transfer and experimental validation
title_short Design of MMP-1 inhibitors via SAR transfer and experimental validation
title_sort design of mmp-1 inhibitors via sar transfer and experimental validation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9719525/
https://www.ncbi.nlm.nih.gov/pubmed/36463250
http://dx.doi.org/10.1038/s41598-022-25079-4
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