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Drug Discovery: Overview

Drug Discovery: Overview

Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...

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Updated: May 5, 2026

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Published on: November 11, 2016

Creating a more strategic small molecule biophysical hit characterization workflow.

Christopher Fotsch¹, Debaleena Basu², Ryan Case²

¹Lead Discovery and Characterization Group, Amgen Research, Thousand Oaks CA, USA.

SLAS Discovery : Advancing Life Sciences R & D

|May 9, 2024

Summary

This summary is machine-generated.

A new workflow using thermal shift assay (TSA) followed by surface plasmon resonance (SPR) or temperature-related intensity change (TRIC) assays improves hit quality. Biophysically confirmed hits demonstrate better drug-likeness and solubility than unconfirmed hits.

Keywords:

Hit characterization Hit quality Hit triaging Target engagement

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Published on: May 16, 2021

Area of Science:

Biochemistry
Drug Discovery
Chemical Biology

Background:

High-throughput screening (HTS) generates numerous hits requiring validation.
Biophysical assays are crucial for confirming target engagement.
Optimizing hit validation workflows is essential for efficient drug discovery.

Purpose of the Study:

To evaluate a refined biophysical assay workflow for hit validation.
To assess the impact of a sequential TSA/SPR or TSA/TRIC assay strategy on hit quality.
To compare the characteristics of biophysically confirmed versus unconfirmed hits.

Main Methods:

Implemented a workflow prioritizing thermal shift assay (TSA) followed by surface plasmon resonance (SPR) or temperature-related intensity change (TRIC) assays.
Analyzed hundreds of hits from 15 HTS campaigns.
Assessed compound quality using quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility.

Main Results:

The TSA/SPR or TSA/TRIC workflow successfully confirmed target engagement for selected hits.
Biophysically confirmed hits exhibited superior performance in compound quality metrics compared to unconfirmed hits.
The refined workflow enriched for higher-quality drug candidates.

Conclusions:

A sequential biophysical assay strategy enhances the efficiency and quality of hit validation in drug discovery.
This workflow not only confirms target engagement but also selects for compounds with improved drug-like properties.
Strategic application of TSA, SPR, and TRIC assays leads to a more robust hit identification process.