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Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies
Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discoverin...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468367/ https://www.ncbi.nlm.nih.gov/pubmed/30901950 http://dx.doi.org/10.3390/cells8030269 |
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author | Rampogu, Shailima Baek, Ayoung Park, Chanin Son, Minky Parate, Shraddha Parameswaran, Saravanan Park, Yohan Shaik, Baji Kim, Ju Hyun Park, Seok Ju Lee, Keun Woo |
author_facet | Rampogu, Shailima Baek, Ayoung Park, Chanin Son, Minky Parate, Shraddha Parameswaran, Saravanan Park, Yohan Shaik, Baji Kim, Ju Hyun Park, Seok Ju Lee, Keun Woo |
author_sort | Rampogu, Shailima |
collection | PubMed |
description | Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors. |
format | Online Article Text |
id | pubmed-6468367 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64683672019-04-23 Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies Rampogu, Shailima Baek, Ayoung Park, Chanin Son, Minky Parate, Shraddha Parameswaran, Saravanan Park, Yohan Shaik, Baji Kim, Ju Hyun Park, Seok Ju Lee, Keun Woo Cells Article Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors. MDPI 2019-03-21 /pmc/articles/PMC6468367/ /pubmed/30901950 http://dx.doi.org/10.3390/cells8030269 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 Rampogu, Shailima Baek, Ayoung Park, Chanin Son, Minky Parate, Shraddha Parameswaran, Saravanan Park, Yohan Shaik, Baji Kim, Ju Hyun Park, Seok Ju Lee, Keun Woo Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title | Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title_full | Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title_fullStr | Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title_full_unstemmed | Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title_short | Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies |
title_sort | discovery of small molecules that target vascular endothelial growth factor receptor-2 signalling pathway employing molecular modelling studies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468367/ https://www.ncbi.nlm.nih.gov/pubmed/30901950 http://dx.doi.org/10.3390/cells8030269 |
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