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N-Methyl-D-aspartic acid (NMDA) receptor is a promising target for treatment of neurodegenerative diseases and other brain disorders as well as for designing proneurogenic compounds able to stimulate neurogenesis in adult brain. We analyzed the structure of the binding site of negative allosteric modulators in the amino-terminal domain of the NMDA receptor and identified possible modes of their binding as well as performed molecular design of new modulators that significantly differ from the known ones in structure and binding mode. In addition, we formed a focused library of chemical compounds with potential neuroprotective and proneurogenic properties, desirable set of pharmacokinetic properties, and low toxicity, which can be the basis for development of new-generation drugs.

The hERG potassium channel is one of the most important anti-targets determining cardiotoxicity of potential drugs. Using fragmental descriptors and artificial neural networks, the predictive models of the relationship between the structure of organic compounds and their activity with respect to hERG were built, and the structural factors affecting it were analyzed. By their predictive ability and applicability domain, these models (N = 1000, Q 2 = 0.77, RMSE cv = 0.45 for affinity and N = 2886, Q 2 = 0.60, RMSE cv = 0.55 for channel inhibition) are superior to the previously published models and can be used to minimize the risk of cardiotoxicity during drug development.

Using fragmental descriptors and artificial neural networks, a predictive model of the relationship between the structure of organic compounds and their blood-brain barrier permeability was constructed and the structural factors affecting the readiness of this penetration were analyzed. This model (N = 529, Q 2 = 0.82, RMSE cv = 0.32) surpasses the previously published models in terms of the prediction accuracy and the applicability domain and can be used for the optimization of the pharmacokinetic parameters during drug development.

A positive allosteric modulator of AMPA receptors has been designed using computer-aided molecular modeling techniques. It possessed a record high experimentally confirmed potency in the picomolar concentration range and belongs to a new type of bivalent AMPA receptor ligands containing bicyclo[3.3.1]nonane scaffold. The suggested structure could serve as a basis for further optimization and development of drugs for the treatment of neurodegenerative diseases, cognition enhancement, and improvement of memory.