Structure-based selection of building blocks for array synthesis via the World-Wide Web

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Structure-based drug design requires efficient methods for selecting chemical entities for synthesis.
• Exploring the conformational space of potential drug molecules is crucial for predicting binding interactions.
• Identifying favorable conformations within a protein's binding site is key to successful drug development.

Purpose of the Study:

• To develop and present an extended conformational searching algorithm for selecting chemical substituents in structure-based design.
• To enable the identification of non-interacting conformations within a fixed binding site.
• To facilitate the quantification of molecule-protein interactions and the retention of promising substituents.

Main Methods:

• Extension of a conformational searching algorithm to enumerate substituents for a fixed template.
• Exploration of conformational space within the protein binding site to identify favorable interactions.
• Quantification of interactions using calculated properties and a web-based interface for non-expert users.
• Illustration of the approach using penicillin-based HIV-1 protease inhibitors.

Main Results:

• The algorithm successfully enumerates and filters substituents based on conformational compatibility within the binding site.
• A web-based interface allows for easy searching, visualization (VRML), and cluster analysis of results.
• The method efficiently identifies potential drug candidates by considering both conformation and binding site interactions.

Conclusions:

• The developed computational approach enhances the selection of chemical entities for array synthesis in structure-based design projects.
• The method, including its user-friendly interface, aids in identifying viable drug candidates, as demonstrated with HIV-1 protease inhibitors.
• This approach provides a valuable tool for medicinal chemists in the drug discovery pipeline.