Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design
 

Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design

Systematic optimization of large macrocyclic peptide ligands is a serious challenge. Here, we describe an approach for lead-optimization using the PD-1/PD-L1 system as a retrospective example of moving from initial lead compound to clinical candidate. We show how conformational restraints can be derived by exploiting NMR data to identify low-energy solution ensembles of a lead compound. Such restraints can be used to focus conformational search for analogs in order to accurately predict bound...

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