Nuclear magnetic resonance and molecular modeling study on mycophenolic acid: Implications for binding to inosine monophosphate dehydrogenase

Gergely M. Makara, György M. Keserû, M. Kajtár-Peredy, Wayne K. Anderson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The conformation of the sodium salt of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPD), derived from 1D DIFNOE and 2D ROESY experiments in water and molecular dynamics (MD) is described. The hexenoic acid side chain conformation consistent with the NMR data was similar to that seen in the X-ray structure of MPA. The solution conformation was applied in a molecular modeling study in order to explore the potential features of enzyme binding. Our results, based on striking similarities in molecular volume and electrostatic isopotential between MPA and cofactor NAD+, lead to the suggestion that MPA is capable of binding to the nicotinamide site of IMPD and mimicking the NAD+ inverse regulation of the enzyme. In addition, our proposed model is in good agreement with the observed high affinity of the dinucleotide analogues thiazole- and selenazole-4-carboxamide adenine dinucleotide to IMPD.

Original languageEnglish
Pages (from-to)1236-1242
Number of pages7
JournalJournal of Medicinal Chemistry
Volume39
Issue number6
DOIs
Publication statusPublished - Mar 15 1996

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Mycophenolic Acid
Inosine Monophosphate
Molecular modeling
Oxidoreductases
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
Conformations
NAD
Thiazoles
Niacinamide
Adenine
Enzymes
Molecular Dynamics Simulation
Static Electricity
Molecular dynamics
Electrostatics
Salts
Sodium
X-Rays
X rays

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Nuclear magnetic resonance and molecular modeling study on mycophenolic acid : Implications for binding to inosine monophosphate dehydrogenase. / Makara, Gergely M.; Keserû, György M.; Kajtár-Peredy, M.; Anderson, Wayne K.

In: Journal of Medicinal Chemistry, Vol. 39, No. 6, 15.03.1996, p. 1236-1242.

Research output: Contribution to journalArticle

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