Structure‐Based Approach To Improve a Small‐Molecule Inhibitor by the Use of a Competitive Peptide Ligand

Abstract

Structural information about the target-compound complex is invaluable in the early stage of drug discovery. In particular, it is important to know into which part of the initial compound additional interaction sites could be introduced to improve its affinity. Herein, we demonstrate that the affinity of a small-molecule inhibitor for its target protein could be successfully improved by the constructive introduction of the interaction mode of a competitive peptide. The strategy involved the discrimination of overlapping and non-overlapping peptide-compound pharmacophores by the use of a ligand-based NMR spectroscopic approach, INPHARMA. The obtained results enabled the design of a new compound with improved affinity for the platelet receptor glycoprotein VI (GPVI). The approach proposed herein efficiently combines the advantages of compounds and peptides for the development of higher-affinity druglike ligands.

Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide

“…As R1 has high binding affinity and makes extensive interactions with the hydrophobic cleft of AMA1, characterization of the AMA1-R1 interaction provides valuable insights into the key interactions that contribute to binding. Indeed, there are many examples showing that small molecule inhibitors can be designed that mimic the interaction of a peptide with a protein target [32] – [37] . In the current study we have undertaken a detailed biophysical characterization of the interaction of R1 with AMA1 and used computational solvent mapping to identify hot spots at the binding interface.…”

Current NMR Techniques for Structure-Based Drug Discovery

“…For effective PPI modulators, peptide-like compounds have promising potential since they can mimic or complement the structural and electrostatic environment of the complex PPI interface. Methodologies for the preparation of NMR-oriented peptide libraries, and NMR-based drug development from peptides by NMR measurements of cross-correlated relaxation (CCR) of the peptidic ligands, have been developed by Takahashi et al [ 46 , 162 , 163 , 164 ]. The design of novel lead compounds that mimic pharmacophores of the PPI modulator peptide is one potential strategy that can be used [ 65 , 165 ].…”

“…20 ns), respectively, the intra-ligand NOE becomes 20 times stronger if the ligand interacted with the protein [ 36 ]. Therefore, protein-ligand interactions can be assessed by NOE-based methods, such as saturation-transfer difference (STD) [ 39 , 40 ], SOS-NMR [ 41 ], WaterLOGSY and its related methods [ 42 , 43 ], transferred NOE (trNOE) [ 44 ], INPHARMA [ 45 , 46 ], and inter-ligand NOE (ILOE) [ 47 ]. These methods use NOE and magnetization transfer from the target protein or other molecules, such as bulk water and ligand, to ligands through dipole–dipole interactions ( Figure 2 ).…”

“…Interligand NOEs for Pharmacophore Mapping (INPHARMA) [ 45 , 46 ] and Inter-ligand nuclear Overhauser effect (ILOE) [ 47 ] methods are based on ligand-to-ligand NOEs via target protein ( Figure 2 e). With the INPHARMA method, inter-ligand NOEs between two ligands, that competitively bind to the same binding site on the target protein, are measured.…”

“…The INPHARMA method determines the relative orientation of two individual ligands if the molecular orientation of one ligand on the target protein is already known [ 45 , 46 ]. By measuring the INPHARMA spectrum of two ligands, even if the conformation or orientation of both ligands are unknown, the correct binding modes of the two ligands and their pharmacophore can be determined by combined use of docking analyses and back-calculation of the INPHARMA spectrum, using the CORCEMA approach [ 49 , 52 , 53 ].…”