Structural Superimposition

Abstact

As ligand molecular weight increases, strategic structural optimization becomes increasingly important because larger ligands contain more modifiable atoms, making comprehensive exploration impractical. We present the structure-activity relationship (SAR) analysis of LUNA18 (paluratide, an 11-mer macrocyclic peptide RAS inhibitor) focusing on the amino acid side chains at position 5 in the solvent-exposed region. The analysis revealed that the contribution of position 5 to inhibitory activity depends on its local environment. Structural analysis identified two structural features: peptides forming a ''cavity'', which possess the hydrophobic interaction network among positions 1, 8, and 9, exhibited minimal changes upon position 5 modification, whereas those forming a ''groove'', lacking this interaction network, showed significant differences. These findings provide practical guidelines for optimizing macrocyclic peptides: evaluate the contributions of solvent-exposed side chain at key points and interpret SARs in the context of spatially proximal side chains.