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dc.contributor.author
Lavecchia, Martín José
dc.contributor.author
Puig de la Bellacasa, Ramón
dc.contributor.author
Borrell, José I.
dc.contributor.author
Cavasotto, Claudio Norberto
dc.date.available
2019-10-07T17:57:19Z
dc.date.issued
2016-02-15
dc.identifier.citation
Lavecchia, Martín José; Puig de la Bellacasa, Ramón; Borrell, José I.; Cavasotto, Claudio Norberto; Investigating molecular dynamics-guided lead optimization of EGFR inhibitors; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 24; 4; 15-2-2016; 768-778
dc.identifier.issn
0968-0896
dc.identifier.uri
http://hdl.handle.net/11336/85286
dc.description.abstract
The epidermal growth factor receptor (EGFR) is part of an extended family of proteins that together control aspects of cell growth and development, and thus a validated target for drug discovery. We explore in this work the suitability of a molecular dynamics-based end-point binding free energy protocol to estimate the relative affinities of a virtual combinatorial library designed around the EGFR model inhibitor 6{1} as a tool to guide chemical synthesis toward the most promising compounds. To investigate the validity of this approach, selected analogs including some with better and worse predicted affinities relative to 6{1} were synthesized, and their biological activity determined. To understand the binding determinants of the different analogs, hydrogen bonding and van der Waals contributions, and water molecule bridging in the EGFR-analog complexes were analyzed. The experimental validation was in good qualitative agreement with our theoretical calculations, while also a 6-dibromophenyl-substituted compound with enhanced inhibitory effect on EGFR compared to the reference ligand was obtained.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Pergamon-Elsevier Science Ltd
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
HIT-TO-LEAD OPTIMIZATION
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LIGAND BINDING FREE ENERGY CALCULATION
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MM/GBSA
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MOLECULAR DOCKING
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MOLECULAR DYNAMICS
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PYRIDO[2,3-D]PYRIMIDINE
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SMALL-MOLECULE INHIBITOR
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Otras Ciencias Químicas
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Ciencias Químicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Investigating molecular dynamics-guided lead optimization of EGFR inhibitors
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-10-02T14:27:29Z
dc.journal.volume
24
dc.journal.number
4
dc.journal.pagination
768-778
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Lavecchia, Martín José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
dc.description.fil
Fil: Puig de la Bellacasa, Ramón. Universitat Ramon Llull; España
dc.description.fil
Fil: Borrell, José I.. Universitat Ramon Llull; España
dc.description.fil
Fil: Cavasotto, Claudio Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
dc.journal.title
Bioorganic & Medicinal Chemistry
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S096808961530211X
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.bmc.2015.12.046


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