A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.

The development of new drugs with potential therapeutic applications is one of the most complex and difficult process in the pharmaceutical industry. Millions of dollars and man-hours are devoted to the discovery of new therapeutical agents. As, the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity and metabolism, rational drug design has been utopias for centuries. Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences and molecular biology have made rational drug design feasible. The aim of this review is to give an outline of studies in the field of medicinal chemistry in which molecular modeling has helped in the discovery process of new drugs. The emphasis will be on lead generation and optimization.

Monoamine oxidase (MAO) is a key enzyme responsible for the degradation of serotonin, norepinephrine, dopamine, and phenylethylamine. It is an outer membrane mitochondrial enzyme existing in two isoforms, A and B. We have recently generated 14 site-directed mutants of human MAO A and B, and we found that four key amino acids, Lys-305, Trp-397, Tyr-407, and Tyr-444, in MAO A and their corresponding amino acids in MAO B, Lys-296, Trp-388, Tyr-398, and Tyr-435, play important roles in MAO catalytic activity. Based on the polyamine oxidase three-dimensional crystal structure, it is suggested that Lys-305, Trp-397, and Tyr-407 in MAO A and Lys-296, Trp-388, and Tyr-398 in MAO B may be involved in the non-covalent binding to FAD. Tyr-407 and Tyr-444 in MAO A (Tyr-398 and Tyr-435 in MAO B) may form an aromatic sandwich that stabilizes the substrate binding. Asp-132 in MAO A (Asp-123 in MAO B) located at the entrance of the U-shaped substrate-binding site has no effect on MAO A nor MAO B catalytic activity. The similar impact of analogous mutants in MAO A and MAO B suggests that these amino acids have the same function in both isoenzymes. Three-dimensional modeling of MAO A and B using polyamine oxidase as template suggests that the overall tertiary structure and the active sites of MAO A and B may be similar.Monoamine oxidase (MAO, 1 EC 1.4.3.4; amine:oxygen oxidoreductase (deaminating, flavin-containing)) is a flavoprotein located at the outer membranes of mitochondria in neuronal, glial, and other cells. It catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine and appears to play important roles in several psychiatric and neurological disorders (for review see Refs. 1 and 2). In addition, it is also responsible for the biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into 1-methyl-4-phenylpyridinium, a Parkinsonian producing neurotoxin (3-5). Recently, it has been shown that MAO may contribute to the apoptotic process because inhibition of MAO activity suppressed cell death (6).MAO exists in two forms, namely MAO A and MAO B. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine) and is irreversibly inhibited by low concentrations of clorgyline (7). MAO B preferentially oxidizes phenylethylamine (PEA) and benzylamine, and it is irreversibly inactivated by low concentrations of pargyline and deprenyl (8). Dopamine, tyramine, and tryptamine are common substrates for both MAOs. MAO A and B consist of 527 and 520 amino acids, respectively, and have a 70% identity (9). Each isoenzyme has a FAD covalently linked to a cysteine residue, Cys-406 in MAO A and Cys-397 in MAO B, through an 8␣-(cysteinyl)-riboflavin (10 -13). They exhibit identical exon-intron organization, and they are probably derived from the duplication of a common ancestral gene (14 Recently, the x-ray crystal structure of a related enzyme namely polyamine oxidase (PAO) has been obtained (25). PAO catalyzes the oxidation of the secondary amino group of polyamines, such as sp...

We report a four-component partial least squares discriminant analysis (PLS) model for the prediction of blood-brain barrier (BBB) permeation using descriptors derived from 3D molecular fields. The 3D fields were transformed by VolSurf into suitable 1D descriptors, which were correlated to the ratio of blood-brain partitioning measured at steady state in rats (log C(brain)/C(blood)). The model so obtained sheds light on molecular properties influencing BBB permeation. It can also be used in the virtual screening of new chemicals.