Biophysics: for HTS hit validation, chemical lead optimization, and beyond

ABSTRACT

Introduction: There are many challenges to the drug discovery process, including the complexity of the target, its interactions, and how these factors play a role in causing the disease. Traditionally, biophysics has been used for hit validation and chemical lead optimization. With its increased throughput and sensitivity, biophysics is now being applied earlier in this process to empower target characterization and hit finding.

Areas covered: In this article, the authors provide an overview of how biophysics can be utilized to assess the quality of the reagents used in screening assays, to validate potential tool compounds, to test the integrity of screening assays, and to create follow-up strategies for compound characterization. They also briefly discuss the utilization of different biophysical methods in hit validation to help avoid the resource consuming pitfalls caused by the lack of hit overlap between biophysical methods.

Expert opinion: The use of biophysics early on in the drug discovery process has proven crucial to identifying and characterizing targets of complex nature. It also has enabled the identification and classification of small molecules which interact in an allosteric or covalent manner with the target. By applying biophysics in this manner and at the early stages of this process, the chances of finding chemical leads with novel mechanisms of action are increased. In the future, focused screens with biophysics as a primary readout will become increasingly common.

KEYWORDS:

• Biophysics
• screening
• hit validation
• chemical lead optimization
• covalent modification
• allosteric
• thermal shift assays
• surface plasmon resonance
• cellular thermal shift assays

Article highlights

• Utilization of biophysics to characterize targets and tool compounds prior to screening can aid in creating the best suited screen for a particular target class.

• Application of biophysics in hit finding can expedite the discovery of novel chemical and probe target engagement.

• Utilization of biophysics enhances the effectiveness of innovative concepts in drug discovery such as the hunt for allosteric effectors and covalent modifiers.

• Placement of biophysics in the drug discovery process requires understanding the weaknesses and strengths of each technology, such that their usage will verify true hits.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Sandra Cowan-Jacob and Kirk Clark for their thoughtful review of the manuscript and valuable suggestions.

Declaration of interest

CC Genick and SK Wright are both employees of Novartis Pharma AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are funded by Novartis Pharma AG.