Carprofen: a theoretical mechanistic study to investigate the impact of hydrophobic interactions of alkyl groups on modulation of COX-1/2 binding selectivity

Abstract

Development of selective COX-1 and COX-2 was successfully used to overcome GIT side effects of the classical NSAIDs. Currently, virtual screening and docking study were extensively used to design of new potent and safe drug candidates. In this study, four series of carprofen derivatives were designed by isosteric replacement of the-NH-with-O- ,-Sand-CH 2-groups. More than 90 derivatives bearing different alkyl substituents were designed in this study. AutoDock software was used to explore the binding mode, affinity and selectivity of the designed analogs to COX1/2. The results revealed that position and length of alkyl substituents have remarkable effect on the binding mode. Substitution with alkyl groups at C1 and C6 of the four scaffolds improved binding to COX-1, while at C4 enhanced COX-2 binding affinity. Compound 66 displayed the highest binding affinity for COX-1 and COX-2 with ΔG b of 11.2 and 10.15 kcal/mol, respectively. Compound 56 and 99 displayed the highest potential selectivity to COX-1 and COX-2, respectively. Drug-likeness study and synthetic accessibility were evaluated for the most promising analogs. Compound 29 displayed drug-likeness score (DLS) of 0.96 compared to 0.3 for carprofen. Taken together, these results highlighted the importance of hydrophobic interactions in modulation of COX-1/2 binding selectivity of new potential NSAIDs.

Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities

“…The docking procedures were performed according to the previous report 25 . The grid and docking parameter files were prepared according to the previous reports 47–49 . Visualisation of the binding interactions of the new compounds in the active sites of CDK-2 was performed by Discovery studio visualizer 50 .…”

“…The docking studies were done using AutoDock 4.2 46 . Preparation of ligands, proteins, grid, and docking parameter files was done following our previous reports [47][48][49] . The study was performed according to the previous report 25 .…”

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

“…Ligand and protein files were prepared according to the previous report 13 , 29 . Docking and grid parameter files were prepared according to the previous reports 30 , 31 . The top 10 protein–ligand complexes were scored.…”

“…AutoDock (v.4.2) was used to perform the docking study 24 . The study was performed following the previous reports [29][30][31] . Validation of the docking procedures into the selected kinases was also performed according to our previous report 13 .…”

Docking studies of sesquiterpene lactones isolated from Ambrosia maritima L. reveals their potential anti-inflammatory and cytotoxic activities

“…In order to validate the docking procedures, the native ligand (ibuprofen) of COX-1 (pdb: 1EQG) was re-docked into the active site of the enzyme as previously reported (Almalki et al 2019;Gouda and Almalki 2019). The redocked ibuprofen superimposed over the native ligand into COX-1 with RMSD of 0.87 Å.…”