Design and synthesis of new nonpeptide caspase-3 inhibitors

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 directed selection of compounds for a targeted synthesis. The biological screening among synthesized compounds 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 its belonging to large libraries (obtained by means of parallel combinatorial synthesis in solution) facilitates the subsequent optimization of active compounds.

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