Systems Pharmacology based CNS Drug Discovery – Computational Aspects
The major trend in drug discovery research over the last 30 years has been to move resources from in vivo based pharmacology towards more reductionist in vitro based approaches emphasising high through-put, genomic, molecular, mechanistic and target-based aspects as key factors for predicted success. Computational chemistry is easily applied and serves, in many respects, as a cornerstone in this new strategy.
An important driver for this change was the assumption that the new approaches would be more rational. The outcome did not turn out to be an obvious success and a partial rebound has been observed in the field with “new” approaches emerging, most of them still rather reductionist in nature, nevertheless emphasising instead the importance of phenotypic and systemic aspects. Computational biology is becoming increasingly important here, since the biology data generated is much more complex.
This presentation will argue for the need of alternative drug discovery approaches to strengthen and broaden innovation in the pharmaceutical industry. Questions like what is known and what is not known in the field regarding disease progression, disease mechanism, mechanisms of action of drugs, interactions of molecules in condensed phases, and how does the industry and academia deal with these unknowns in their approaches, will be addressed. The systems pharmacology based approach taken in our labs which have resulted in the Integrative Screening Process (ISP) platform will be described in this context. ISP can be described as the engineer’s approach to drug discovery, where empirical observations on complex read-outs from both novel test compounds and compounds with known effects in man are compared in a standardized manner. Furthermore, we will discuss computational chemistry and biology methods, which are central components of ISP, with a choice of methods and their applications that is different compared to the prevailing use of such methods in drug discovery.