CONFIRM: connecting fragments found in receptor molecules

Area of Science:

• Computational chemistry
• Drug discovery
• Structural biology

Background:

• Fragment-based drug design (FBDD) is a powerful strategy for identifying novel drug candidates.
• Connecting small molecular fragments within a target binding site is a critical step in FBDD.
• Existing methods for fragment linking can be computationally intensive and lack automation.

Purpose of the Study:

• To introduce a novel algorithm, CONFIRM (Connecting Fragments Found in Receptor Molecules), for automated fragment molecule connection.
• To validate the CONFIRM algorithm's performance on various test systems.
• To discuss the general applicability of CONFIRM in fragment-based de novo drug design.

Main Methods:

• Development of the CONFIRM algorithm, which searches a library of molecular bridges.
• Matching bridge candidates to search criteria derived from fragment binding information.
• Automated connection of fragments with selected bridges and subsequent docking into the target receptor.
• Assessment of docking poses using root-mean-squared deviation and docking scores.

Main Results:

• Successful validation of the CONFIRM algorithm across multiple test systems.
• Demonstration of automated fragment connection and docking capabilities.
• The algorithm effectively identifies and connects suitable molecular bridges.

Conclusions:

• The CONFIRM algorithm presents a novel and automated approach for connecting fragment molecules.
• This method shows significant potential for advancing fragment-based de novo drug design.
• CONFIRM offers a valuable tool for accelerating the drug discovery process.