Biomedical Engineering Reference
In-Depth Information
FIGURE 12.3
Stages of HTS-based lead identification and optimization projects.
Confirmed compounds are normally resupplied in dry powder; their purity, chem-
ical identity, and biological activity are confirmed in hit validation stage. In the lead
characterization stage, the compounds are confirmed and profiled using secondary
biological assays as well as the assays for appropriate counter-targets to establish
specificity. Structure-activity relationship (SAR) and mechanism of action (MOA)
studies, also part of lead characterization, allow identification of the scaffolds pos-
sessing the desired properties. In the lead optimization stage, several rounds of SAR
are performed to optimize the desired attributes of the lead compounds. For exam-
ple, lead compounds within drug discovery projects are usually tested in a standard
in vitro pharmacology panel to establish and optimize compounds' solubility and
stability and eliminate undesired reactivity.
Depending on the number of compounds passing through the various stages,
several shortcuts could be utilized to speed up the process (depicted with arrows
on the left side in Figure 12.3). A large number of primary hits could be profiled
directly at the single-concentration stage with respect to their specificity, selectivity,
and MOA attributes. This shortcut allows an enrichment of the hit set with compounds
possessing the desired properties. On the other hand, a hit list containing only a small
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