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Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening

[Image: see text] Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the...

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Autores principales: Gomez-Gutierrez, Patricia, Rubio-Martinez, Jaime, Perez, Juan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598794/
https://www.ncbi.nlm.nih.gov/pubmed/37824186
http://dx.doi.org/10.1021/acs.jcim.3c01212
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author Gomez-Gutierrez, Patricia
Rubio-Martinez, Jaime
Perez, Juan J.
author_facet Gomez-Gutierrez, Patricia
Rubio-Martinez, Jaime
Perez, Juan J.
author_sort Gomez-Gutierrez, Patricia
collection PubMed
description [Image: see text] Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1–P8) in K-Ras, four of which (P1–P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 μM.
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spelling pubmed-105987942023-10-26 Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening Gomez-Gutierrez, Patricia Rubio-Martinez, Jaime Perez, Juan J. J Chem Inf Model [Image: see text] Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1–P8) in K-Ras, four of which (P1–P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 μM. American Chemical Society 2023-10-12 /pmc/articles/PMC10598794/ /pubmed/37824186 http://dx.doi.org/10.1021/acs.jcim.3c01212 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Gomez-Gutierrez, Patricia
Rubio-Martinez, Jaime
Perez, Juan J.
Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title_full Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title_fullStr Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title_full_unstemmed Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title_short Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening
title_sort discovery of hit compounds targeting the p4 allosteric site of k-ras, identified through ensemble-based virtual screening
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598794/
https://www.ncbi.nlm.nih.gov/pubmed/37824186
http://dx.doi.org/10.1021/acs.jcim.3c01212
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