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Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D

With the success rate of drugs for CNS indications at an all-time low, new approaches are needed to turn the tide of failed clinical trials. This paper reviews the history of CNS drug Discovery over the last 60 years and proposes a new paradigm based on the lessons learned. The initial wave of succe...

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Autores principales: Geerts, Hugo, Barrett, James E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646593/
https://www.ncbi.nlm.nih.gov/pubmed/31379482
http://dx.doi.org/10.3389/fnins.2019.00723
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author Geerts, Hugo
Barrett, James E.
author_facet Geerts, Hugo
Barrett, James E.
author_sort Geerts, Hugo
collection PubMed
description With the success rate of drugs for CNS indications at an all-time low, new approaches are needed to turn the tide of failed clinical trials. This paper reviews the history of CNS drug Discovery over the last 60 years and proposes a new paradigm based on the lessons learned. The initial wave of successful therapeutics discovered using careful clinical observations was followed by an emphasis on a phenotypic target-agnostic approach, often leading to successful drugs with a rich pharmacology. The subsequent introduction of molecular biology and the focus on a target-driven strategy has largely dominated drug discovery efforts over the last 30 years, but has not increased the probability of success, because these highly selective molecules are unlikely to address the complex pathological phenotypes of most CNS disorders. In many cases, reliance on preclinical animal models has lacked robust translational power. We argue that Quantitative Systems Pharmacology (QSP), a mechanism-based computer model of biological processes informed by preclinical knowledge and enhanced by neuroimaging and clinical data could be a new powerful knowledge generator engine and paradigm for rational polypharmacy. Progress in the academic discipline of computational neurosciences, allows one to model the effect of pathology and therapeutic interventions on neuronal circuit firing activity that can relate to clinical phenotypes, driven by complex properties of specific brain region activation states. The model is validated by optimizing the correlation between relevant emergent properties of these neuronal circuits and historical clinical and imaging datasets. A rationally designed polypharmacy target profile will be discovered using reverse engineering and sensitivity analysis. Small molecules will be identified using a combination of Artificial Intelligence methods and computational modeling, tested subsequently in heterologous cellular systems with human targets. Animal models will be used to establish target engagement and for ADME-Tox, with the QSP approach complemented by in vivo preclinical models that can be further refined to increase predictive validity. The QSP platform can also mitigate the variability in clinical trials with the concept of virtual patients. Because the QSP platform integrates knowledge from a wide variety of sources in an actionable simulation, it offers the possibility of substantially improving the success rate of CNS R&D programs while, at the same time, reducing both cost and the number of animals.
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spelling pubmed-66465932019-08-02 Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D Geerts, Hugo Barrett, James E. Front Neurosci Neuroscience With the success rate of drugs for CNS indications at an all-time low, new approaches are needed to turn the tide of failed clinical trials. This paper reviews the history of CNS drug Discovery over the last 60 years and proposes a new paradigm based on the lessons learned. The initial wave of successful therapeutics discovered using careful clinical observations was followed by an emphasis on a phenotypic target-agnostic approach, often leading to successful drugs with a rich pharmacology. The subsequent introduction of molecular biology and the focus on a target-driven strategy has largely dominated drug discovery efforts over the last 30 years, but has not increased the probability of success, because these highly selective molecules are unlikely to address the complex pathological phenotypes of most CNS disorders. In many cases, reliance on preclinical animal models has lacked robust translational power. We argue that Quantitative Systems Pharmacology (QSP), a mechanism-based computer model of biological processes informed by preclinical knowledge and enhanced by neuroimaging and clinical data could be a new powerful knowledge generator engine and paradigm for rational polypharmacy. Progress in the academic discipline of computational neurosciences, allows one to model the effect of pathology and therapeutic interventions on neuronal circuit firing activity that can relate to clinical phenotypes, driven by complex properties of specific brain region activation states. The model is validated by optimizing the correlation between relevant emergent properties of these neuronal circuits and historical clinical and imaging datasets. A rationally designed polypharmacy target profile will be discovered using reverse engineering and sensitivity analysis. Small molecules will be identified using a combination of Artificial Intelligence methods and computational modeling, tested subsequently in heterologous cellular systems with human targets. Animal models will be used to establish target engagement and for ADME-Tox, with the QSP approach complemented by in vivo preclinical models that can be further refined to increase predictive validity. The QSP platform can also mitigate the variability in clinical trials with the concept of virtual patients. Because the QSP platform integrates knowledge from a wide variety of sources in an actionable simulation, it offers the possibility of substantially improving the success rate of CNS R&D programs while, at the same time, reducing both cost and the number of animals. Frontiers Media S.A. 2019-07-16 /pmc/articles/PMC6646593/ /pubmed/31379482 http://dx.doi.org/10.3389/fnins.2019.00723 Text en Copyright © 2019 Geerts and Barrett. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Geerts, Hugo
Barrett, James E.
Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title_full Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title_fullStr Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title_full_unstemmed Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title_short Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D
title_sort neuronal circuit-based computer modeling as a phenotypic strategy for cns r&d
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646593/
https://www.ncbi.nlm.nih.gov/pubmed/31379482
http://dx.doi.org/10.3389/fnins.2019.00723
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