Discovery of hit compounds

The discovery of hit compounds determines the starting point of the entire drug discovery process and is of vital importance. The confirmation stage of the hit compound is as follows:

Exclude compounds with potential reactivity, interference with testing, or self-aggregation.

Repeated activity test: For the selected target, the active compound obtained by high-throughput screening is repeatedly tested for activity under the same conditions.

Measure the dose-response relationship curve: calculate the IC50 or EC50 value.

If homologues are available, conduct a structure-activity relationship (SAR) study.

Is the binding to the target reversible?

Orthogonal test: Use test conditions close to the actual physiological environment of the target or other different methods to test the activity of the hit compound.

Secondary screening: biological function test (agonist/antagonist) or cell test to confirm activity.

Evaluation of druggability: use calculation methods to predict or preliminarily test the physicochemical properties and ADME properties of emerging compounds.

Chemical ease of handling: From the perspective of a medicinal chemist, evaluate the compound’s synthetic feasibility and stability in different chemical environments.

Intellectual property evaluation: search the patent situation of the hit compound in a specific database to ensure that it is not protected by intellectual property.

Sorting and clustering of hit compounds, preliminary SAR analysis.

Activity confirmation experiments include classic dose response curves, no cumulative effects (incubation effects), stability to mild reducing agents, and specificity to selected targets.

If a molecule is labeled as a potential PAINS or polymer based on published data, but can pass these activity confirmation experiments, it may be a good hit compound.

Finally, the structure-activity relationship (SAR) study combined with the mechanism of the system can provide the most convincing evidence for the reaction specificity of the hit compound. Covalent molecules and molecules with optical interference will work through specific physical mechanisms, but such interference can be eliminated through controlled experiments. Currently, colloidal aggregation can be determined by rapid mechanical testing and counter-screening.

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Hit Identification in Drug Discovery