Max Planck Society Background
For designing high affinity drug candidates from weakly bound lead compounds, the relative orientation of two competitive ligands A and B in the receptor binding pocket plays a central role. In a two state kinetic model the free ligands A and B bind competitively to a target T forming the complex TA or TB ().
Through spatial proximity between the ligand protons and the proteins of the target receptor Nuclear Overhauser Enhancement (NOE) is mediated by spin diffusion through the target protein. Such signatures become particularly apparent in NOESY spectra (Nuclear Overhauser Enhancement and exchange Spectroscopy) gained by nuclear magnetic resonance (NMR) spectroscopy.
Scientists from the Max Planck Institute for Biophysical Chemistry and European Molecular Biology Laboratory (EMBL) have developed the INPHARMA methodology that utilizes NOESY spectra recorded of two competitively binding ligands. It distinguishes among different binding modes of a ligand to a macromolecular target, if the binding mode of a second competitive ligand is known. Thus, it allows for rapid determination of the binding epitope of different ligands to a common target.
The algorithm implemented in the INPHARMA software calculates from a structural model of two inhibitor/protein complexes with a given rotational correlation time the NOE that is mediated through spatial proximity between the ligand protons and protons of the target molecule. The correlation time of the complex and the amount of bound ligand is determined from quantification of transferred NOEs between the protons within the ligands. It further allows incorporating mobility of groups in the target.
V. Sanchez-Pedregal et al., “The INPHARMA method: Protein-mediated interligand NOEs for pharmacophore mapping”, Angew. Chem. Int. Ed., 2005 (44), 4172–4175, DOI: 10.1002/anie.200500503
J. Orts, C. Griesinger, and T. Carlomagno, “The INPHARMA technique for pharmacophore mapping: A theoretical guide to the method”, J. Magn. Reson., 2009 (200), 64–73 (2009), DOI: 10.1016/j.jmr.2009.06.006
S. Bartoschek et al., “Drug design for G-protein-coupled receptors by a ligand-based NMR method”, Angew. Chem. Int. Ed., 2010 (49), 1426–1429, DOI: 10.1002/anie.200905102
Quantitative analysis of ligand binding.
The software allows selecting those binding poses that fit best to INPHARMA, STD and transfer NOE data.
Faster and more efficient than existing software that uses spin diffusion methods for small molecules/protein complexes.