PROSTAGLANDIN AND BRADYKININ MECHANISMS OF ANALGESIC AND ANTI-INFLAMMATORY ACTION OF PROPOXAZEPAM: MOLECULAR DOCKING DATA

Abstract

Introduction. Prostaglandins and bradykinin are important compounds involved in the onset and transmission of pain. Innovative drug propoxazepam, created at the Institute of Physical Chemistry of the National Academy of Sciences of Ukraine and SLC "INTERCHEM" has an original pharmacodynamic profile, as it simultaneously inhibits acute and chronic pain with components of anti-inflammatory and anticonvulsant action.

The aim of the study – to learn the possibility of propoxazepam interaction with cyclooxygenases I and II and the bradykinin receptor based on the results of molecular docking.

Research Methods. The molecular docking procedure was performed using iGEMDOCK v2.1, the structure of the compounds was optimized for the internal energy (Avogadro (v 1.2.0) and presented in *.pdb format).

Results and Discussion. The values of free energy of interaction of propoxazepam and some reference compounds with macromolecules of COX I, COX II and bradykinin were calculated, and the amino acid residues involved in these processes were determined. The interaction energy of propoxazepam with COX I and COX II was found to be lower than for other reference compounds. The average binding energy of COX I compared to the reference compounds (acetylsalicylate, ketorolac, diclofenac, celecoxib) is the lowest for propoxazepam.

Conclusions. Based on the obtained molecular docking data, it can be concluded that propoxazepam does not interact sufficiently with the key enzyme of prostaglandin synthesis – COX I (mostly weak Van-der-Waals bonds are formed, and the identified sites of interaction are nonspecific). Interaction with COX II may be ineffective because the binding sites are located close to the active site and involve amino acid residues of the same domain. Antagonism with interaction with the type 1 bradykinin receptor is likely, as evidenced by the same binding sites for the endogenous ligand bradykinin and the high mean binding energy.