Jean-Marie Contreras

Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q2LOO=0.937, q2L50% O=0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model.

Homo and Heterodimer Ligands: the Twin Drug Approach

Publisher Summary Drugs containing two pharmacophoric groups covalently bounded are called twin drugs. This chapter focuses on the combination of only two (identical or nonidentical) pharmacological entities. The association of two identical pharmacophoric entities will generate an “identical twin drug” which is equivalent to a homodimer derivative. The first design strategy is equivalent to a duplication/dimerization process of an active compound or lead. The aim of this approach is the production of a more potent and/or more selective drug compared to the single entity. The administration of twin drugs can be favorable compared to the two separated drugs. The new entity has its own pharmacokinetic property (absorption, distribution, and metabolism) and pharmacodynamic property. These properties will be more predictable compared to the administration of two separated drugs. The duplication of the pharmacophore leads to an equivalent or more active derivative, which exhibits a different selectivity profile and pharmacokinetic properties. Identical twin drugs have shown increasing potencies and/or modified selectivity profiles as receptor ligands when compared to their corresponding single drug. Medicinal chemists should take into account the use of the twin drug approach as soon as they get a lead compound that needs to be optimized.

16 – IDENTICAL AND NON-IDENTICAL TWIN DRUGS

Drugs containing two pharmacophoric groups covalently bounded in a single molecule are called twin drugs. The combination of two identical pharmacophoric entities will lead to an identical twin drug, whereas the association of two different drug entities will generate a nonidentical twin drug. The first strategy consists of molecular variations based on duplication, while the second one results from associative synthesis. Identical and nonidentical twin drugs may be combined by a linker, a no linker, or in overlap mode. The spacer group can be a single bond, a polymeric chain, or in somes cases, an aromatic or nonaromatic cycle. Identical twin drugs may have different modes of connection of the two drug entities. Referring to polymer chemistry nomenclature, each molecule can be formally represented with a head and a tail. Thus, a head-to-head, a tail-to-tail or a head-to-tail connection is possible. The first and the second modes generate symmetrical compounds, which represent the major part of the identical twin drugs described in the literature. However, nonsymmetrical drugs, such as amentoflavone, are not uncommon. Nonidentical twin drugs are also named dual acting drugs or hybrids because of the different pharmacological responses targeted by the two pharmacophoric moities. The design of dual acting drugs, called the symbiotic approach, can be accomplished according to two strategies.

Comparative Molecular Field Analysis of Aminopyridazine Acetylcholinesterase Inhibitors

Modern methods for computer-assisted drug design fall into two major families — the indirect ligand-based methods, e.g. CoMFA or GOLPE and the direct receptor-based methods including molecular dynamics (MD) simulation, free energy pertubation (FEP) and the various docking procedures. Nowadays the ligand-based methods are widely used since they are computationally not demanding. The main problem of the ligand-based methods is the alignment of the investigated compounds. On the other hand the direct approach yields important information concerning the exact position of the ligands in the binding pocket. Since the MD and FEP methods are computationally intensive, they cannot be applied to large data sets. The faster docking programs on the other hand are at the moment not able to predict correctly the biological activity. One possibility to overcome these problems seems to be the combination of both approaches — merging the accuracy of the receptor-based strategies with the efficiency of modern 3D-QSAR techniques. This strategy has recently successfully applied by several groups1.