Abstract
Computer visualisation of the active site of monoamine oxidase (MAO) is based on an assumption that the specific and reversible interaction of a ligand (substrate or inhibitor) with the substrate-binding region of the active site requires shape complementarity. The size of the ligand must allow its accommodation at the substrate-binding region. Analysis of the MAO-inhibitory activity of rigid analogues of isatin and pirlindole revealed a dependence between three-dimensional linear sizes of these molecules and the efficacy of inhibition of both MAO-A and MAO-B. However, flexible molecules did not exhibit any dependence between linear sizes and MAO-B inhibitory potency, possibly because they folded into compact structures could fit into the substrate-binding pocket of MAO-B. 'Moulding' of the substrate/inhibitor binding region by superposition of effective MAO-A inhibitors from various groups of chemicals allowed the shape of substrate/inhibitor binding region to be visualised. 'Removal of contents' from this mould yielded a cavity, which corresponded to the shape of substrate/inhibitor binding region. Such cavity can be used to evaluate the most probable positions known inhibitors take in binding to it. The docking procedure can also be used for searching molecular databases for new inhibitors. Pilot experiments revealed that relatively rigid compounds, which did not fit to this cavity, were poor inhibitors of MAO-A.
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REFERENCES
Bach, A. W. J., Lan, N. C., Johnson, D. L., Abell, C. W., Bembeneck, M. E., Kwan, S. W., Seeburg, P. H. and Shih, J. H. (1988). cDNA Cloning of Human Liver Monoamine Oxidase A and B: Molecular Basis of Differences in Enzymatic Properties, Proc. Natl. Acad. Sci. USA 85, 4934–4938.
Cesura, A. M., Gottowik, J., Lang, G., Malherbe, P. and Da Prada M. (1998). Structure-function relationships of mitochondrial monoamine oxidase A and B: chimeric enzymes and site-directed mutagenesis studies, J. Neural Transm. 52 (Suppl.), 189–200.
Cesura, A. M. and Pletscher A. (1992). The new generation of monoamine oxidase inhibitors, Progr. Drug Res. 38, 171–297.
Gorkin, V. Z. (1983). Amine Oxidases in Clinical Research, Pergamon Press, Oxford.
Krueger, M. J., Efange, S. M., Michelson, R. H. and Singer, T. P. (1992). Interaction of flexible analogues of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridineand of N-methyl-4-phenylpyridinium with highly purified monoamine oxidase A and B, Biochemistry 31, 5611–5615.
Krueger, M. J., Mazouz, F., Ramsay, R. R., Milcent, R. and Singer, T. P. (1995). Dramatic species differences in the susceptibility of monoamine oxidase B to a group of powerful inhibitors, Biochem. Biophys. Res. Comm. 206, 556–562.
Medvedev, A., Gorkin, V., Shvedov, V., Fedotova, O., Fedotova, I. and Semiokhina, A. (1992). Efficacy of pirlindole, a highly selective reversible inhibitor of monoamine oxidase type A, in the prevention of experimentally induced epileptic seizures, Drug Invest. 4, 501–507.
Medvedev, A. E., Ivanov, A. S., Kamyshanskaya, N. S., Kirkel, A. Z., Moskvitina, T. A., Gorkin, V. Z., Li, N. Y. and Marshakov, V. Yu. (1995). Interaction of indole derivatives with monoamine oxidase A and B. Studies on the Structure–Inhibitory activity relationship, Biochem. Mol. Biol. Internat. 36, 113–122.
Medvedev, A. E., Ivanov, A. S., Veselovsky, A. V., Skvortsov, V. S. and Archakov, A. I. (1996). QSAR Analysis of Indole Analogues as Monoamine Oxidase Inhibitors, J. Chem. Inform. Comput. Sci. 36, 664–671.
Medvedev, A. E., Ramsay, R. R., Ivanov, A. S., Veselovsky, A. V., Shvedov, V. I., Tikhonova, O. V., Barradas, A.-P. V., Davidson, C. K., Moskvitina, T. A., Fedotova, O. A. and Axenova, L. N. (1999). Inhibition of monoamine oxidase by pirlindole analogues: 3D-QSAR analysis, Neurobiology 7, 151–158.
Medvedev, A. E., Veselovsky, A. V., Shvedov, V. I., Tikhonova, O. V., Moskvitina, T. A., Fedotova, O. A., Axenova, L. N., Kamyshanskaya, N. S., Kirkel, A. Z. and Ivanov, A. S. (1998). Inhibition of monoamine oxidase by pirlindole analogues: 3D-QSAR and CoMFA analysis, J. Chem. Inform. Comput. Sci. 38, 1137–1144.
Panova, N. G., Zemskova, M. A., Axenova, L. N. and Medvedev, A. E. (1997). Does isatin interact with rat brain monoamine oxidases in vivo?, Neurosci. Lett. 233, 58–60.
Shih, J. C., Chen, K. and Ridd, M. J. (1999). Monoamine oxidase: from genes to behavior, Annu. Rev. Neurosci. 22, 197–217.
Singer, T. P. (1985). Inhibitors of FAD-containing monoamine oxidases, in: Structure and Functions of Amine Oxidases, Mondovi, B. (Ed.), pp. 219–230. CRC Press, Boca Raton, FL.
Singer, T. P. and Ramsay, R. R. (1993). New aspects of the substrate specificities, kinetic mechanisms and inhibition of monoamine oxidase, in: Monoamine Oxidase: Basic and Clinical Aspects, Yasuhara, H., Parvez, S. H., Oguchi, K., Sandler, M. and Nagatsu, T. (Eds), pp. 23–43. VSP, Utrecht.
Singer, T. P. and Ramsay, R. R. (1995). Monoamine oxidases: old friends hold many surprises, FASEB J. 5, 605–610.
Tsugeno, Y. and Ito, A. (1997). A key amino acid responsible for substrate selectivity of monoamine oxidase A and B, J. Biol. Chem. 272, 14033– 14036.
Veselovsky, A. V., Ivanov, A. S. and Medvedev, A. E. (1998). Is one amino acid responsible for substrate specificity of monoamine oxidase A and B, Biochemistry (Moscow) 63, 1695–1701.
Veselovsky, A. V., Medvedev, A. E., Tikhonova, O. V., Skvortsov, V. S. and Ivanov, A. S. (2000). Modelling of substrate-binding region of the active site of monoamine oxidase A, Biochemistry (Moscow) 65, 910–916.
Wouters, J. (1998). Structural aspects of monoamine oxidase and its reversible inhibition, Curr. Med. Chem. 5, 137–162.
Wouters, J., Moureau, F., Vercauteren, D. P., Evrard, G., Durant, F., Koenig, J. J., Duerey, F. and Jarreau, F. X. (1994). Experimental and theoretical study of reversible monoamine oxidase inhibitors: structural approach of the active site of the enzyme, J. Neural Transm. 41 (Suppl.), 313–319.
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Medvedev, A.E., Ivanov, A.S. & Veselovsky, A.V. Computer visualisation of the active site of monoamine oxidase-A by means of selective inhibitors. Inflammopharmacology 11, 135–143 (2003). https://doi.org/10.1163/156856003765764308
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DOI: https://doi.org/10.1163/156856003765764308