NUCLEAR-MAGNETIC-RESONANCE AND MOLECULAR MODELING STUDY ON MYCOPHENOLIC-ACID - IMPLICATIONS FOR BINDING TO INOSINE MONOPHOSPHATE DEHYDROGENASE

The conformation of the sodium salt of mycophenolic acid (MPA), a pote nt inhibitor of inosine monophosphate dehydrogenase (IMPD), derived fr om 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consisten t, with the NMR data was similar to that seen in the X-ray structure o f MPA. The solution conformation was applied in a molecular modeling s tudy in order to explore the potential features of enzyme binding. Our results, based on striking similarities in molecular volume and elect rostatic isopotential between MPA and cofactor NAD(+), lead to the sug gestion that MPA is capable of binding to the nicotinamide site of IMP D and mimicking the NAD(+) inverse regulation of the enzyme. In additi on, our proposed model is in good agreement with the observed high aff inity of the dinucleotide analogues thiazole- and selenazole-4-carboxi mide adenine dinucleotide to IMPD.