Structure–Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region

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.