Comparative analysis of protein-ligand interactions of NSAIDs as cyclooxygenase inhibitors

Abstract

Features of the structure of the active binding site of both isoforms (similarity and specificity), the com- plexity of the supramolecular interactions of NSAIDs and expected safety features of the new generation NSAIDs remain relevant. The specificity of the supramolecular interactions of NSAIDs, as COX inhibitors, is an important element of the system for evaluating biological effects in medical technologies aimed at the search for new drugs.

Zones of amino acid residues important for the position of the ligand in the active binding site were deter- mined. In general, according to the results of the comparative analysis, it was found that in the active binding site of COX-1 and COX-2, such residues as «Arg120, Val349, Leu352, Tyr355, Leu359», «Tyr385, Trp387», «Phe518, Ile523», surround the molecules of traditional NSAIDs. They are common features important for three zones of amino acid residues: the non-selective binding site (at the entrance to the channel), the site of competitive inhibition (catalytic center) and the site of hydrophobic interactions (near the Phe518/Ile523 residues) (with closed access to the secondary internal space in the active site of COX-1). A specific feature of the active binding site is a zone with open access to the secondary internal space with Arg499 (celecoxib) or Arg513 (SC558 and etoricoxib), which provides ligand – enzyme interaction of specific COX-2 inhibitors. An important feature of some ligands (NSAID molecules) is the inversion of the pose in COX-1 against the pose in COX-2, which explains the peculiarities of their pharmacological properties.