Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors

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dc.contributor.authorMellado, Marco
dc.contributor.authorGonzález, César
dc.contributor.authorMella, Jaime
dc.contributor.authorAguilar, Luis F.
dc.contributor.authorViña, Dolores
dc.contributor.authorUriarte, Eugenio
dc.contributor.authorCuellar, Mauricio
dc.contributor.authorMatos, Maria J.
dc.date.accessioned2022-11-30T02:46:34Z
dc.date.available2022-11-30T02:46:34Z
dc.date.issued2021
dc.description.abstractMonoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was −10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.en_ES
dc.facultadFacultad de Cienciasen_ES
dc.file.nameMellado_Com2021.pdf
dc.identifier.doihttps://doi.org/10.1016/j.bioorg.2021.104689
dc.identifier.urihttp://repositoriobibliotecas.uv.cl/handle/uvscl/7423
dc.languageen
dc.publisherElsevier
dc.rights© 2021 Elsevier Inc. All rights reserved.
dc.sourceBioorganic Chemistry
dc.subjectCHALCONE DERIVATIVESen_ES
dc.subjectMONOAMINE OXIDASE B INHIBITORSen_ES
dc.subject3D-QSAR MODELSen_ES
dc.subjectMOLECULAR DOCKINGen_ES
dc.subjectDRUG DESIGNen_ES
dc.titleCombined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors
dc.typeArticulo
uv.departamentoInstituto de Quimica y Bioquimica
uv.notageneralNo disponible para descarga

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