Empirical Analysis of Drug Targets for Nervous System Disorders

The discovery and development of
drugs to treat diseases
of the
nervous system remains challenging. There is a higher attrition rate
in the clinical stage for nervous system experimental drugs compared
to other disease areas. In the preclinical stage, additional challenges
arise from the considerable effort required to find molecules that
penetrate the blood–brain barrier (BBB) coupled with the poor
predictive value of many preclinical models of nervous system diseases.
In the era of target-based drug discovery, the critical first step
of drug discovery projects is the selection of a therapeutic target
which is largely driven by its presumed pathogenic involvement. For
nervous system diseases, however, the feasibility of identifying potent
molecules within the stringent range of molecular properties necessary
for BBB penetration should represent another important factor in target
selection. To address the latter, the present review analyzes the
distribution of human protein targets of FDA-approved drugs for nervous
system disorders and compares it with drugs for other disease areas.
We observed a substantial difference in the distribution of therapeutic
targets across the two clusters. We expanded on this finding by analyzing
the physicochemical properties of nervous and non-nervous system drugs
in each target class by using the central nervous system multiparameter
optimization (CNS MPO) algorithm. These data may serve as useful guidance
in making more informed decisions when selecting therapeutic targets
for nervous system disorders.