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1.
Toxicol Appl Pharmacol ; 407: 115244, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32961130

RESUMEN

Nuclear receptors (NRs) are key regulators of human health and constitute a relevant target for medicinal chemistry applications as well as for toxicological risk assessment. Several open databases dedicated to small molecules that modulate NRs exist; however, depending on their final aim (i.e., adverse effect assessment or drug design), these databases contain a different amount and type of annotated molecules, along with a different distribution of experimental bioactivity values. Stemming from these considerations, in this work we aim to provide a unified dataset, NURA (NUclear Receptor Activity) dataset, collecting curated information on small molecules that modulate NRs, to be intended for both pharmacological and toxicological applications. NURA contains bioactivity annotations for 15,247 molecules and 11 selected NRs, and it was obtained by integrating and curating data from toxicological and pharmacological databases (i.e., Tox21, ChEMBL, NR-DBIND and BindingDB). Our results show that NURA dataset is a useful tool to bridge the gap between toxicology- and medicinal-chemistry-related databases, as it is enriched in terms of number of molecules, structural diversity and covered atomic scaffolds compared to the single sources. To the best of our knowledge, NURA dataset is the most exhaustive collection of small molecules annotated for their modulation of the chosen nuclear receptors. NURA dataset is intended to support decision-making in pharmacology and toxicology, as well as to contribute to data-driven applications, such as machine learning. The dataset and the data curation pipeline can be downloaded free of charge on Zenodo at the following DOI: https://doi.org/10.5281/zenodo.3991561.


Asunto(s)
Bases de Datos Factuales , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Química Farmacéutica/métodos , Simulación por Computador , Recolección de Datos , Interpretación Estadística de Datos , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Bibliotecas de Moléculas Pequeñas , Programas Informáticos , Toxicología/métodos
2.
Molecules ; 25(13)2020 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-32605289

RESUMEN

Chromatographic profiles of primary essential oils (EO) deliver valuable authentic information about composition and compound pattern. Primary EOs obtained from Pinus sylvestris L. (PS) from different global origins were analyzed using gas chromatography coupled to a flame ionization detector (GC-FID) and identified by GC hyphenated to mass spectrometer (GC-MS). A primary EO of PS was characterized by a distinct sesquiterpene pattern followed by a diterpene profile containing diterpenoids of the labdane, pimarane or abietane type. Based on their sesquiterpene compound patterns, primary EOs of PS were separated into their geographical origin using component analysis. Furthermore, differentiation of closely related pine EOs by partial least square discriminant analysis proved the existence of a primary EO of PS. The developed and validated PLS-DA model is suitable as a screening tool to assess the correct chemotaxonomic identification of a primary pine EOs as it classified all pine EOs correctly.


Asunto(s)
Aceites Volátiles/análisis , Pinus sylvestris/química , Análisis Discriminante , Diterpenos/análisis , Diterpenos/química , Cromatografía de Gases y Espectrometría de Masas , Estructura Molecular , Aceites de Plantas/análisis , Sesquiterpenos/análisis , Sesquiterpenos/química
3.
ChemMedChem ; 14(12): 1129-1134, 2019 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-30973672

RESUMEN

A virtual screening protocol based on machine learning models was used to identify mimetics of the natural product (-)-galantamine. This fully automated approach identified eight compounds with bioactivities on at least one of the macromolecular targets of (-)-galantamine, with different polypharmacological profiles. Two of the computer-generated hits possess an expanded spectrum of bioactivity on targets relevant to the treatment of Alzheimer's disease and are suitable for hit-to-lead expansion. These results advocate multitarget drug design by advanced virtual screening protocols based on chemically informed machine learning models.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Productos Biológicos/farmacología , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Galantamina/farmacología , Aprendizaje Automático , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Productos Biológicos/síntesis química , Productos Biológicos/química , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Evaluación Preclínica de Medicamentos , Galantamina/síntesis química , Galantamina/química , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estereoisomerismo
4.
J Med Chem ; 61(12): 5442-5447, 2018 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-29901398

RESUMEN

Natural products (NPs) are progressively recognized as invaluable source of pharmacological tools and lead structures. To enable NP-inspired retinoid X receptor (RXR) modulator design, three novel RXR-targeting NPs were computationally identified. Among them, valerenic acid was found to be selective for RXRß, rendering it a unique pharmacological tool compound. The NPs then served as templates for automated, ligand-based de novo design of innovative, easily accessible mimetics that inherited the biological activities of their natural templates.


Asunto(s)
Productos Biológicos/química , Biología Computacional/métodos , Indenos/farmacología , Receptores X Retinoide/metabolismo , Sesquiterpenos/farmacología , Abietanos/química , Abietanos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Células Hep G2 , Humanos , Indenos/química , Ligandos , Fenantrenos/química , Fenantrenos/farmacología , Receptores X Retinoide/agonistas , Receptores X Retinoide/química , Sesquiterpenos/química
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