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Molecular Imaging Branch

2.8 Quantum chemistry

2 Research Method Development

2.8 Quantum chemistry

The discovery of PET radiotracers for protein targets usually operates blind with respect to a detailed knowledge of the structure of the protein target and of the ligand-protein interaction at the molecular level. This is a general impediment to efficient discovery of ligands, and hence radiotracers. We are collaborating with Dr. Y.-S. Lee (Center for Information Technology, NIH) to use powerful quantum chemistry techniques (e.g. Gaussian 03; B3LYP/6-31G) to establish the preferred conformations of receptor ligands and their modes of recognition by targeted binding sites. Studies were initiated on the binding of ligands to peripheral (PBR) and central (CBR) benzodiazepine binding sites. Our calculations on the energy barriers for E/Z rotational isomerization in classical PBR ligands (e.g. the isoquinoline carboxamide, PK 11195; 20) are wholly consistent with results from our temperature 1H- and 13C-NMR studies, which enable us to hypothesize that PBR preferentially recognizes the E-rotamer (20a) over the Z-rotamer (20b).55 This hypothesis, if verified experimentally, may have important consequences for understanding the topography of the PBR binding site and possibly of its function, as well as for ligand design.