Identification of potential drug-like molecules for inhibition of the inflammatory activity of cyclooxygenase-2

Abstract

Inflammation plays a pivotal role in all stages of atherosclerosis and therefore targeting the key enzymes of this pathway may help in ameliorating the disease progression. The current study is aimed to identify small lead molecules as a promising inhibitor for the cyclooxygenase-2 (COX-2), a therapeutically important protein involved in the prostaglandin biosynthesis pathway and a key player in driving the inflammatory atherogenic progression. Herein, we have used extensive computational methods such as virtual screening, protein–ligand docking, molecular dynamics simulation and binding free energy analysis. Out of 2500 molecules, 1408 compounds have favourable drug-like properties. ZINC72348892 showed GOLD fitness score of 86.38 with COX-2 and established two hydrogen bonds with Phe519 and mostly hydrophobic interactions. The second lead ZINC72295579 showed GOLD fitness score of 84.07 with COX-2 and exhibited four hydrogen bonds with His90, Tyr356, Tyr386 and Ala528. Both the lead compounds exhibit high binding affinity for COX-2 compared with COX-1 isoenzyme. Further, the lead molecules showed a favourable Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) Gibbs binding free energy lower compared to the control. Van der Waal energy is the predominant component driving the interaction of the lead molecules with COX-2. Essential dynamics and entropy calculation further confirmed the structural rigidity and compactness of the protein upon binding of the lead molecules. Thus our findings suggest that ZINC72348892 and ZINC72295579 as promising lead molecules for inhibition of COX-2 and which would provide alternative chemotypes in the drug discovery pipeline for the treatment of cardiovascular diseases.AbbreviationsCVDsCardiovascular diseasesCOXCyclooxygenaseMDMolecular dynamicsMM/PBSAMolecular mechanics Poisson–Boltzmann surface areaROFRule of fiveNVTNumber of particles, volume and temperatureNPTNumber of particles, pressure and temperatureRMSDRoot mean square deviationRMSFRoot mean square fluctuationSASASolvent accessible surface areaRgRadius of gyrationPCAPrincipal component analysisEDEssential dynamicsNHBsNumber of hydrogen bondsCommunicated by Ramaswamy H. Sarma