ИСТИНА

Molecular modelling and molecular dynamics simulation are critically important in the analysis of drug-target interactions on the molecular level and in the design of new molecules which bind in the most optimal way to a particular target (usually to either enzyme or receptor). This kind of studies is very popular nowadays and their results are quite fruitful: practically all newly developed drugs passed this stage of studies. However, the interactions of small molecules with so “big” targets as proteins usually cannot be treated on the quantum chemistry level while molecular mechanics used in this case has intrinsic restrictions. The combined QM/MM approaches also do not always help. It is shown that the inclusion of additional parameters into the force fields taking into account the non-classical nature of interactions (which play the main role in “conformational effects”, halogen bonding, etc.) significantly improves the situation. Special attention in this presentation is paid to the use of “unusual” conformational behavior (conformational effects) in the design of molecules (drug candidates) pre-organized for optimal binding with particular targets. The molecular modelling and molecular dynamics simulation of the receptors of glutamatergic and GABAergic systems and their ligands are discussed. The designed ligands have demonstrated a high potency in experimental in vitro and in vivo studies.