Abstract
Several studies have revealed that phthalides are suitable scaffolds for the design of high potency monoamine oxidase (MAO) inhibitors, in which C6-substituted phthalides have been shown high binding affinities to the MAO-A and MAO-B isoenzyme without delineating the underlying mechanism. By means of molecular modeling, we proposed a structural basis of such activity, in which these compounds could successfully dock into the active pocket of human MAO isoforms with predicted affinities in comparison to phthalide. Our study indicated that the interaction of hydrogen bond was more important factor for C6-substituted phthalides binding to MAO-A, and the orientations of inhibitors and the bound residues had the major impact on the binding to MAO-B. These results, therefore, suggested that C6-substituted phthalides served as promising leads for the development of drug treatments to neurodegenerative disorders such as Parkinson’s disease.
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Acknowledgments
We thank Professor Arthur J. Olson for his kindness in offering us the AUTODOCK 4.2 program. We also gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC, No. 21275067).
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Li, P.Z., Tian, Y.L., Zhai, H.L. et al. Molecular modeling study on the structural basis of binding mechanism of C6-substituted phthalides with monoamine oxidases. Med Chem Res 23, 3624–3631 (2014). https://doi.org/10.1007/s00044-014-0941-0
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DOI: https://doi.org/10.1007/s00044-014-0941-0