LigEvolutioner, a new strategy for modification and optimization of lead compounds in receptor/ligand complexes

With the number of solved protein/ligand complex 3D structures growing up rapidly in recent years, lead modification and optimization based on the complex structure have received much attention in drug design community. In this study, we propose a novel method LigEvolutioner for the purpose of lead optimization in protein/ligand complexes. Using a fragment substitution strategy in the context of evolutionary algorithm, LigEvolutioner can analyze the complex structures automatically and derive several modification projects that could possibly improve the binding affinity of ligands. For instance, LigEvolutioner was employed to analyze and modify antigenic peptide ligand in human HLA-A*0201/peptide complexes and, as a result, a peptide analogue with potential high affinity was designed. The structure configuration of this modified peptide is consistent with crystal profile and antigen presenting theory. In addition, we have confirmed the validity of LigEvolutioner by systematically comparing it with several widely used scoring methods.