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 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