A perspective on the changing landscape of HTS

Area of Science:

• Drug discovery and medicinal chemistry
• Biochemistry and structural biology

Background:

• Early drug discovery portfolios increasingly include challenging targets previously considered intractable.
• These targets often feature shallow or absent ligand-binding sites, disordered structures, or are involved in protein-protein/DNA interactions.

Purpose of the Study:

• To review the evolving landscape of drug target selection in early discovery.
• To discuss the necessary adaptations in screening strategies and chemical approaches.
• To provide insights into future requirements for small-molecule hit and lead generation.

Main Methods:

• Literature review of recent trends in drug discovery target selection.
• Analysis of changes in screening methodologies.
• Examination of evolving drug modalities and medicinal chemistry requirements.

Main Results:

• A significant rise in the proportion of challenging drug targets.
• Necessity for altered screening approaches to identify hits for these targets.
• Expansion in the diversity of drug modalities and associated medicinal chemistry.

Conclusions:

• The field of drug discovery is shifting towards more complex and historically intractable targets.
• Adaptations in screening technologies and medicinal chemistry are crucial for success.
• Future efforts must focus on innovative strategies for small-molecule hit and lead generation against these difficult targets.