Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2

Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.