Modeling of Substrate-Binding Region of the Active Site of Monoamine Oxidase A

A. V. Veselovsky^*, A. E. Medvedev, O. V. Tikhonova, V. S. Skvortsov, and A. S. Ivanov

Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Pogodinskaya ul. 10, Moscow, 119832 Russia; fax: (095) 245-0768; E-mail: veselov@ibmh.msk.su

^* To whom correspondence should be addressed.

Received March 1, 2000; Revision received April 10, 2000

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The mold of the substrate-binding region of the active site of monoamine oxidase A (MAO A) was designed using data of the enzyme interaction with reversible competitive inhibitors and the analysis of their three-dimensional structures. The superposition of ligands in biologically active conformations allowed determination of the shape and dimension of the active site cavity accommodating these compounds. The correctness of this approach was validated by the analysis of HIV protease interaction with its inhibitors using three-dimensional structures of HIV protease-inhibitor complexes. The mold of the substrate/inhibitor-binding site can be used for searching for new ligands in molecular databases and the development of a new generation of MAO inhibitors using lead structures that have not been employed for this purpose yet.

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KEY WORDS: monoamine oxidase A, reversible inhibitors, active site, computer modeling, three-dimensional structure, molecular database

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