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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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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.
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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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