The article summarized results of studies on active site structures of monoamine oxidases (MAO) performed in the Institute of Biomedical Chemistry (Russia) by computer modelling approaches. MAO, catalyzing the reaction of oxidative deamination of major neurotransmitter monoamines, exists in two highly homologous forms, MAO A and MAO B, distinguished by substrate specificity and inhibitor selectivity. The development of approaches for active site modelling of these enzymes (with unknown three-dimensional structures) started from analysis of relationship between the geometrical sizes of rigid indole and isatin derivatives and their inhibitory activity. These studies resulted in molding of the active site structures of MAO A and MAO B. These molds reflect the sizes and shapes of active sites of these enzymes. These mold models have been used for virtual screening of molecular databases for new inhibitors. The models obtained at different stages of MAO investigations have been compared with recently appeared three-dimensional structures of MAO A and MAO B.
Obobshcheny rezul'taty mnogoletneĭ raboty po issledovaniiu struktury aktivnykh tsentrov monoaminoksidaz (MAO) metodami komp'iuternogo modelirovaniia, vypolnennykh v Institute biomeditsinskoĭ khimii (IBMKh). MAO prisutstvuet v organizme mlekopitaiushchikh v vide dvukh vysokogomologichnykh belkov (MAO A i MAO B), otlichaiushchikhsia po substratnoĭ spetsifichnosti, ingibitornoĭ selektivnosti i drugim svoĭstvam. Pokazano razvitie podkhodov po modelirovaniiu struktury aktivnykh tsentrov fermentov s neizvestnoĭ prostranstvennoĭ strukturoĭ na osnove selektivnykh ingibitorov. Otpravnoĭ tochkoĭ issledovaniĭ posluzhila obnaruzhennaia zavisimost' mezhdu geometricheskimi razmerami konformatsionno zhestkikh molekul ingibitorov i velichinoĭ ikh ingibitornoĭ aktivnosti. Posleduiushchie raboty priveli k sozdaniiu modeli slepka aktivnogo tsentra, kotoryĭ otrazhal geometricheskie razmery i formu aktivno go tsentra. Pokazana vozmozhnost' ego ispol'zovaniia dlia poiska novykh ingibitorov v molekuliarnykh bazakh dannykh. Privedeny rezul'taty raboty po poisku selektivnykh i neselektivnykh ingibitorov MAO. Provedeno sravnenie poluchennykh modeleĭ so strukturoĭ aktivnykh tsentrov kristallicheskikh struktur MAO, poluchennykh pozdnee.
Keywords: MAO; active site; computer modelling; inhibitors; monoamine oxidase.