Structural stability of diclofenac vs. inhibition activity from ab initio molecular dynamics simulations. Comparative study with ibuprofen and ketoprofen

Abstract

Diclofenac is the world known nonsteroidal anti-inflammatory drug (NSAID) predicted before its syntesis on the basis of the model COX enzyme. Due to its specific structural properties the drug possesses high reactivity and outstanding tolerability. Among the key features defining the diclofenac structure is intramolecular N-H ⋯O hydrogen bond confirmed during the X-ray analysis. In the present research we use static DFT calculations, the Quantum Theory of Atoms in Molecules and non-covalent interactions (NCI) index to confirm the additional intramolecular interactions, which influence the drug molecular structure. We focus on the structural stability of diclofenac as the result of the hydrogen bonds breaking/formation at finite temperature utilizing ab initio molecular dynamics simulations. The lifetime of different intramolecular hydrogen bonds is estimated. We perform also the comparative analysis of the structural stability of ibuprofen and ketoprofen molecules in the gas phase at 300 K with respect to diclofenac in terms of the NSAID inhibition activity. Due to the detailed description of diclofenac intramolecular interactions, possible drug modifications for its enhanced water solubility can be suggested.