Recent developments in de novo design and scaffold hopping

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• De novo ligand design, established in 1991, initially used structure-based methods and later incorporated ligand-based approaches.
• Both methods focus on identifying pharmacophores and shape constraints to match small-molecule topologies.
• Scaffold hopping has transitioned from a specialized technique to a widely adopted strategy in the pharmaceutical industry.

Purpose of the Study:

• To review the evolution and recent developments in de novo ligand design and scaffold hopping.
• To highlight the integration of computational methods with experimental techniques like fragment screening and X-ray crystallography.
• To underscore the growing importance and application of these techniques in pharmaceutical research.

Main Methods:

• Review of literature and software tools in de novo ligand design and scaffold hopping since 2006.
• Analysis of structure-based and ligand-based computational approaches.
• Examination of combined strategies involving biophysical fragment screening and X-ray structure elucidation.

Main Results:

• Significant advancements in de novo ligand design, integrating structure- and ligand-based strategies.
• Increased focus on combining de novo design with experimental biophysical fragment screening and structural data.
• Expansion of scaffold hopping from a niche area to a broadly applied suite of software tools.
• Extensive utilization of these computational tools within the pharmaceutical industry for drug discovery.

Conclusions:

• De novo ligand design and scaffold hopping have matured significantly, offering powerful tools for drug discovery.
• The synergy between computational design and experimental validation is crucial for success.
• Scaffold hopping is now an indispensable part of modern pharmaceutical research and development.