IN-SILICO STUDY: COX2 (CYCLO-OXYGENASE 2), AN UNKNOWN TARGET OF HYDROXYCHLOROQUINE REPOSITIONED FOR THE TREATMENT OF COVID 19 INFECTION AND CARDIOVASCULAR EFFECTSAbstract
Hydroxychloroquine, widely used to treat certain autoimmune diseases and inflammatory conditions, has been repositioned as a new lead against the COVID-19 pandemic. Preliminary studies have suggested that hydroxychloroquine inhibits the entry of the SARS-CoV2 virus mediated by the ACE2 receptor and is a particularly interesting anti-inflammatory and immunomodulatory action in the cytokine storm during COVID-19 infection. Furthermore, cardiovascular effects have been reported in hypertensive patients. These last are thought to result from the inhibition of cyclooxygenase 2. Our results reveal for the first time in atomic detail how hydroxychloroquine, one of the most controversial drugs, has an affinity for a new molecular target (COX2) with a docking score: -7.6 (kcal/mol) and a root mean square deviation (RMSD = 2.542). Hydroxychloroquine binds to cyclo-oxygenase 2 via two hydrogen bonds (H-GLY136 and H-GLY45) and four hydrophobic bonds: Cl -CYS36, 0 -CYS36, 0 -CYS47 and 0 -PRO154). This mechanism has never been elucidated. Hydroxychloroquine proved to be promiscuous. Its structure, which differs from that of non-steroidal anti-inflammatory drugs , tends to show activity against a wide variety of biological targets : As an enzyme inhibitor (bioactivity = 0.15), GPCR receptor ligand (bioactivity = 0.35), ion channel modulator (bioactivity = 0.30), kinase inhibitor (bioactivity = 0.44) and protease inhibitor (bioactivity = 0.12). This approach improves the understanding of its mechanism of action and the side effects attributed to it.
H. N. Merad-Boudia *, M. Dali-Sahi, B. Guermouche and N. Dennouni-Medjati
Department of Biology, Analytical Chemistry and Electrochemistry Laboratory, Abou Bekr Belkaid University, Tlemcen, Algeria.
05 October 2020
30 December 2020
31 December 2020
01 February 2021