Химия и химические технологии/ 4. Химико-фармацевтическое производство

Dr.hab. Kucherenko L.I., PhD Khromylova O.V.

Zaporozhye State Medical University, Ukraine

About possibility of L-arginine complexes formation with thiotriazolin

The development of new highly effective and safe neurometobolitotropic cerroprotecters is an actual problem of pharmacy and medicine. Today, cerebral vascular diseases are one of the main causes of morbidity, mortality and disability in the industrialized countries. Currently, neurotransmitter amino acids are used increasingly for correction and regulation of mood, neurological conditions of patients after stroke. They control the main functions of the body, including movement, emotional reactions and physical ability to feel pleasure and pain. The most known neurotransmitter amino acids are: arginine, glycine, taurine, tryptophan, lysine, glutamic acid, etc.

In the development of new drugs, it is promising to create a drug based on a fixed combination of the active ingredient with antioxidants. Tiotriazolin - one of the most famous domestic antioxidants, has antioxidant, membranestabilizing, anti-ischemic, antiarrhythmic, immunomodulating, anti-inflammatory, hepatoprotective, cardioprotective effects. Therefore, the creation of a new combination drug based on L-arginine with tiotriazoline, is of particular interest.

For the joint use of L-arginine with thiotriazoline, it is necessary to consider the possible structure and energy characteristics of the complexes formed by L-arginine, 3-methyl-1,2,4-triazolyl-5-thioacetate (MTTA) and morpholine.

The initial approximation to the structure of the complexes was obtained with the help of molecular docking procedure using the AutoDock Vina program. The resulting three-component complexes were preliminarily optimized by the semiempirical PM7 method, taking into account the outward influences, which was simulated by the COSMO method. The calculations were carried out using the MOPAC2012 program. The complexes were optimized using the density functional method with the empirical dispersion correction B97-D3/SVP+COSMO (Water) using geometric correction for the incompleteness of the gCP basic set. A more accurate calculation of the solvation energy was carried out by SMD method. Calculations by the density functional method were carried out using the ORCA 3.0.3 program. The energy of formation of complexes in solution was calculated as the difference between the free Gibbs energies of the solvated complex and its individual solvated components. The chosen technique with a high degree of probability guarantees finding the most stable three-component complexes.

The compound of morpholine and MTTA is an organic salt. On the other hand, L-arginine, as the amino acid, has to exist in the form of zwitter-ion. However, unlike many other amino acids, L-arginine molecule contains three hydrogen atoms, which may be protonated. Therewith, the L-arginine zwitterionic form acts as both donor and acceptor in the formation of intermolecular hydrogen bonds reinforced with morpholine cation and MTTA anion. This suggests the possibility of both two-component complexes with L-arginine and Thiotriazolin and one of the components and the ternary complexes, involving all three molecules. The multiplicity of donor and acceptor sites in all three studied molecules creates the possibility of the formation of sufficiently large number of possible complexes.

Quantum chemical calculations show that thiotriazolin and L-arginine are able to form ternary complexes, where molecules are linked by multiple hydrogen bonds. From 5 to 7 intermolecular hydrogen bonds are formed in the most stable complexes. In this case, each of the molecules forms hydrogen bonds with the other two in complexes.

The calculation data suggest that studied complexes are thermodynamically unstable in solution. The energies of them are positive, but rather low despite charge gain of a number of intermolecular hydrogen bonds. Apparently, this is due to the high conformational flexibility of the molecules, in which the involved hydrogen bonding groups are separated by a bridge containing several methylene groups, and quite easy transfer of protons involved in hydrogen bonding. It is also possible to affirm the existence of some of the most profitable mode binding in complexes. It should be noted that the solvation energies were calculated in the approximation of infinite dilution. Molecular complexes are expected to be more stable in the final concentration of solution due to strengthening of intermolecular interactions.

Based on the results of the conducted quantum-chemical study of a three components system (MTTA, morpholine, and L-arginine) it is possible to show the possibility to form ternary complexes with low stability in infinite dilute solutions. It should be noted that two negative charges are always localized in formed complexes on the deprotonated carboxyl groups. The positive charges are located either on the guanidine moiety and the α-amino group of L-arginine, or on the guanidine moiety of L-arginine and protonated molecule of morpholine. It can be expected that the strengthening of intermolecular interactions in the real solutions may result in increased stability of the complexes.

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