Biomedical Engineering Reference
In-Depth Information
I.3 THERAPEUTIC TARGETS—IDENTIFICATION AND VALIDATION
Target discovery, which comprises identii cation and validation of disease-modifying targets, is
an essential early step in the drug discovery pipeline. A number of approaches to target discovery
have been described in recent years. These approaches and models incorporate recent technological
advances, such as genomics, proteomics, small interfering RNAs (siRNAs), and mouse gene knock-
out models. In this section of the topic, these aspects of modern drug discovery will be described
in brief (Figure I.2).
The various techniques applied in target identii cation and validation can be grouped into two
broad target discovery strategies: the “molecular” and “systems” approach. In practice, however,
both are used in varying proportions within different therapeutic areas. The “systems” approach
should not be confused with the recent emergence of “systems biology,” which is an attempt to
construct models that explain biological responses using the plethora of information being produced
from the molecular sciences.
The molecular approach is focused on the cells implicated in the disease and uses clinical samples
and cell models. The molecular approach has been driven by the enormous experimental successes
of molecular biology, and in particular genomics. In terms of target classes, the molecular approach
Disease model
Target identiication
Target validation
Drug discovery
Overview
Disease tissue
expression
Clinical
samples
Path A:
Genomics,
proteomics,
genetic association
Drug discovery:
Cell models:
Molecular
approaches
High throughput
screening of
compound
libraries
mRNA KO, protein
overexpression
Cell
models
Forward genetics
Structure-based
drug design
Path B:
Patients
Clinical sciences
Animal models:
Systems
approaches
(conditional) KO,
transgenic mice
Forward genetics
Reverse genetics
Animal models
FIGURE I.2
Target-based drug discovery. Four step overview (top arrows) and detailed schematic outline.
Target-based drug discovery may be divided into molecular- (path A) and system-based (path B) approaches.
Each approach is composed of three steps: the provision of disease models/tissues (red), target identii cation
(purple), and target validation (blue). The molecular approach (path A) comprises techniques such as genom-
ics, proteomics, genetic association, and reverse genetics, whereas systems approach (path B) comprises clini-
cal and other in vivo studies to identify targets. Target validation covers conformational experiments in cell
and/or animal models. Subsequently, the drug discovery process is commenced.
