Abstract
Highly effective computer-aided (virtual) and real biological screening over quinoline derivatives is described, which has led to the discovery of a new structural class of caspase-3 inhibitors. This enzyme (belonging to the group of cysteine proteases) is a promising therapeutically-significant biological target that is involved in the development of various pathological states in the human organism. The virtual screening method is based upon evaluation of a target-specific profile of compounds by means of a special algorithm intended for the analysis of multiparametric data arrays (self-organizing Kohonen maps). Using this approach, it is possible to carry out targeted selection of compounds for the synthesis. The biological screening led to a series of new effective inhibitors of caspase-3, the most active of which possess effective inhibiting concentrations in the range of IC50 = 4 - 30 nM. The nonpeptide nature of the new chemotype offers potentially favorable pharmacokinetic parameters, while the belonging to large libraries (obtained by means of the parallel combinatorial synthesis in solution) facilitates the subsequent optimization of active compounds.
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