In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan
Jorba, Guillem (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Aguirre-Plans, Joaquim (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Junet, Valentin (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Segú-Vergés, Cristina (Anaxomics Biotech SL)
Ruiz, José Luis (Anaxomics Biotech SL)
Pujol, Albert (Anaxomics Biotech SL)
Fernández-Fuentes, Narcís (Universitat de Vic - Universitat Central de Catalunya. Departament de Biociències)
Mas, José Manuel (Anaxomics Biotech SL)
Oliva Miguel, Baldomero (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)

Fecha:	2020
Resumen:	Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models of the mechanism of action of a drug. Each molecular mechanism generated could be associated to particular individuals, here defined as prototype-patients, hence the generation of models using TPMS technology may be used for detecting adverse effects to specific patients. TPMS operates by (1) modelling the responses in humans with an accurate description of a protein network and (2) applying a Multilayer Perceptron-like and sampling strategy to find all plausible solutions. In the present study, TPMS is applied to explore the diversity of mechanisms of action of the drug combination sacubitril/valsartan. We use TPMS to generate a wide range of models explaining the relationship between sacubitril/valsartan and heart failure (the indication), as well as evaluating their association with macular degeneration (a potential adverse effect). Among the models generated, we identify a set of mechanisms of action associated to a better response in terms of heart failure treatment, which could also be associated to macular degeneration development. Finally, a set of 30 potential biomarkers are proposed to identify mechanisms (or prototype-patients) more prone of suffering macular degeneration when presenting good heart failure response. All prototype-patients models generated are completely theoretical and therefore they do not necessarily involve clinical effects in real patients.
Ayudas:	Agencia Estatal de Investigación BIO2017-85329-R Ministerio de Economía y Competitividad RYC-2015-17519 Ministerio de Economía y Competitividad MDM-2014-0370 Ministerio de Economía y Competitividad PT13/0001/0023 European Commission 765912 European Commission 765158 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-00519
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PloS one, Vol. 15, Núm. 2 (February 2020) , art. e0228926, ISSN 1932-6203

DOI: 10.1371/journal.pone.0228926
PMID: 32053711

16 p, 1.4 MB

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