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Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach
As new drugs for the treatment of malignant tumors, transforming growth factor-beta receptor 1 (TGFβR1) antagonists have attracted wide attention. Based on the crystal structure of TGFβR1-BMS22 complex, the pharmacophore model A02 with two hydrogen bond acceptors (HBAs) and four hydrophobic (HYD) pr...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278322/ https://www.ncbi.nlm.nih.gov/pubmed/30384428 http://dx.doi.org/10.3390/molecules23112824 |
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author | Jiang, Junhao Zhou, Hui Jiang, Qihua Sun, Lili Deng, Ping |
author_facet | Jiang, Junhao Zhou, Hui Jiang, Qihua Sun, Lili Deng, Ping |
author_sort | Jiang, Junhao |
collection | PubMed |
description | As new drugs for the treatment of malignant tumors, transforming growth factor-beta receptor 1 (TGFβR1) antagonists have attracted wide attention. Based on the crystal structure of TGFβR1-BMS22 complex, the pharmacophore model A02 with two hydrogen bond acceptors (HBAs) and four hydrophobic (HYD) properties was constructed. From the common features of active ligands reported in the literature, pharmacophore model B10 was also generated, which has two aromatic ring centers (RAs) and two HYD properties. The two models have high sensitivity and specificity to the training set, and they are highly consistent in spatial structure. Combining the two pharmacophore models, two novel skeleton structures with potential activity were selected by virtual screening from the DruglikeDiverse, MiniMaybridge, and ZINC Drug-Like databases. Four compounds (YXY01–YXY04) with potential anti-TGFβR1 activity were designed based on the new skeleton structures. In combination with Lipinski’s rules; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and, toxicological properties predicted in the study, YXY01-03 with the novel skeleton, good drug-like properties, and potential activity were finally discovered and may have higher safety relative to BMS22, which may be valuable for further research. |
format | Online Article Text |
id | pubmed-6278322 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62783222018-12-13 Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach Jiang, Junhao Zhou, Hui Jiang, Qihua Sun, Lili Deng, Ping Molecules Article As new drugs for the treatment of malignant tumors, transforming growth factor-beta receptor 1 (TGFβR1) antagonists have attracted wide attention. Based on the crystal structure of TGFβR1-BMS22 complex, the pharmacophore model A02 with two hydrogen bond acceptors (HBAs) and four hydrophobic (HYD) properties was constructed. From the common features of active ligands reported in the literature, pharmacophore model B10 was also generated, which has two aromatic ring centers (RAs) and two HYD properties. The two models have high sensitivity and specificity to the training set, and they are highly consistent in spatial structure. Combining the two pharmacophore models, two novel skeleton structures with potential activity were selected by virtual screening from the DruglikeDiverse, MiniMaybridge, and ZINC Drug-Like databases. Four compounds (YXY01–YXY04) with potential anti-TGFβR1 activity were designed based on the new skeleton structures. In combination with Lipinski’s rules; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and, toxicological properties predicted in the study, YXY01-03 with the novel skeleton, good drug-like properties, and potential activity were finally discovered and may have higher safety relative to BMS22, which may be valuable for further research. MDPI 2018-10-31 /pmc/articles/PMC6278322/ /pubmed/30384428 http://dx.doi.org/10.3390/molecules23112824 Text en © 2018 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 Jiang, Junhao Zhou, Hui Jiang, Qihua Sun, Lili Deng, Ping Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title | Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title_full | Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title_fullStr | Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title_full_unstemmed | Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title_short | Novel Transforming Growth Factor-Beta Receptor 1 Antagonists through a Pharmacophore-Based Virtual Screening Approach |
title_sort | novel transforming growth factor-beta receptor 1 antagonists through a pharmacophore-based virtual screening approach |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278322/ https://www.ncbi.nlm.nih.gov/pubmed/30384428 http://dx.doi.org/10.3390/molecules23112824 |
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