COMPUTER SEARCH OF CHEMICAL COMPOUNDS – PROPERTIES ANALOGUES FOR PYRROLIDINOPHENONE DERIVATIVES
Authors: I.V. Synbulatov , A.V. Voronin 
Published: December 2020

The study of forensic toxicology of pyrrolidinophenone derivatives is of great importance now. Obtaining sorbents used for selective solid-phase extraction of pyrrolidinophenone derivatives from biological fluids is a new direction of using this method in the analysis practice. Research on the synthesis of selective sorbents is preceded by a choice of a model chemical compound that is not controlled in the Russian Federation, but maximally reproduces the physicochemical properties of pyrrolidinophenone derivatives, as well as their stereochemical characteristics. Pyrrolidinophenone derivatives are narcotic drugs; it means search for a model chemical compound is possible only by means of an in-silico computer experiment. This study is devoted to the search for model chemical compounds with physicochemical properties and stereochemical characteristics similar to pyrrolidinophenone derivatives using computer modeling methods. We studied the structural formulas of "small" molecules - alpha-pyrrolidinovalerophenone and its metabolite 1-(1-oxo-1-phenylpentan-2-yl) pyrrolidin-2-one, 3,4-methylenedioxypyrovalerone and its metabolite 1-[1-(2H-1,3-benzodioxol-5-yl)-1-oxypentan-2-yl] pyrrolidin-2-one as well as phenylpiracetam, pidotimod, brivaracetam, piracetam and levetiracetam. Structural descriptors of molecules were calculated using the ChemAxonPASS program. Ionization constants (pKb), distribution coefficients in the n-octanol-water system at different pH (logD) and water solubility were calculated. Stereochemical interactions of the investigated "small" molecules with serotonin and dopamine receptors were carried out by the molecular docking method using the SwissDock and GOLD programs with genetic algorithms taking into account the ligand conformational mobility. It has been established that phenylpiracetam, pidotimod, brivaracetam, piracetam and levetiracetam will be in molecular form in a wide range of pH values, which corresponds to the behavior of the alpha-pyrrolidinovalerophenone and 3,4-methylenedioxypyrovalerone metabolites. logD value of phenylpiracetam, which is higher than that for other drugs, has the closest value to the logD value for alpha-pyrrolidinovalerophenone. Taking into account the above regularity and water solubility, it should be assumed that the physicochemical properties of phenylpiracetam, which are significant for sample preparation, are sufficiently close to the properties of pyrrolidinophenone derivatives. Stereochemical identity of phenylpiracetam to pyrrolidinophenone derivatives was determined by molecular docking using the following scoring functions — free binding energy (ΔG); a scoring function based on a force field (GoldScore) and a scoring evaluation function (ChemScore). The intermolecular interaction of the studied compounds with the serotonin and dopamine receptors at the binding sites in this case reproduces the interaction with the structures of synthetic sorbents, which is based on van der Waals forces and hydrogen bonds. The high affinity of phenylpiracetam for receptors indicates a stereochemical analogy to pyrrolidinophenone derivatives. Phenylpiracetam can be recommended as a model chemical compound for laboratory studies to obtain synthetic sorbents for solid-phase extraction of pyrrolidinophenone derivatives.