Computer visualisation of the active site of monoamine oxidase-A by means of selective inhibitors

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.