Structure Guided Drug Designing Coupled to Advanced Molecular Dynamics Revealed Differential Binding Properties (Affinity/Stability) of Celecoxib and Niflumic Acid in the Active Site of Cyclooxygenase-2 Enzyme

Abstract Cyclooxygenase-2 (COX-2) has aggressive implications in inflammation triggered disorders such as neurodegeneration and cancer. Among the various inhibitors available for this enzyme celecoxib and niflumic acid are considered as selective inhibitors. These inhibitors have shown in vitro assays have been observed to hamper the COX-2 activity. However, the structural studies at atomistic depth shedding light on diverse aspects of these inhibitors in the binding groove of COX-2 have not been addressed. Thus, in this study we employed structure-governed drug designing approach in concert with real-time molecular dynamics for unravelling the binding likeliness, interaction mechanism and stability of niflumic acid and celecoxib in the COX-2 active site. Our findings indicate the relatively higher binding proclivity and stability of niflumic acid in the active site of COX-2 as compared to celecoxib. Although these inhibitors bind at the same COX-2 site but they revealed differential interaction profile. The outcome from this study will serve as a point of departure for designing novel COX-2 inhibitors with improved potency, selectivity and stability for their subsequent use to vanquish vicious inflammation backed disorders.