Protocol for fragment hopping.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Fragment-based drug design (FBDD) is a powerful approach for identifying biologically active small molecules.
• Determining minimal pharmacophoric elements in three-dimensional space is crucial for FBDD.
• Exploring chemical space and achieving target selectivity are key challenges in drug development.

Purpose of the Study:

• To detail a protocol for performing fragment hopping, a fragment-based design approach.
• To demonstrate how fragment hopping can generate new ligands with novel scaffolds.
• To illustrate the utilization of subtle differences in active sites between isofunctional proteins for enhanced ligand selectivity.

Main Methods:

• Fragment hopping protocol execution.
• Determination of minimal pharmacophoric elements in 3D space.
• Generation and positioning of new fragments to target protein active sites.
• Characterization of active site differences between isofunctional proteins.

Main Results:

• Successful exploration of a wide chemical space.
• Production of new ligands with novel scaffolds.
• Generation of ligands with high target selectivity/specificity by exploiting active site differences.

Conclusions:

• Fragment hopping is an effective strategy for discovering novel drug candidates.
• This approach enables the design of ligands with improved potency and selectivity.
• Fragment hopping offers a versatile platform for advancing drug discovery efforts.