Modeling of 2-Pyridin-3-yl-Benzo[d][1,3]Oxazin-4-one Derivatives by Several Conformational Searching Tools and Molecular Docking

Mohammad      Goodarzi; Alina      Bora; Ana      Borota; Simona      Funar-Timofei; Sorin      Avram; Yvan      Vander Heyden

Abstract

Neutrophil elastase, a serine proteinase from the chymotrypsin family, has been the object of comprehensive experimental and theoretical studies to develop efficient human neutrophil elastase inhibitors. The serine protease has been linked to the pathology of a variety of inflammatory diseases, making it an attractive target for the development of anti-inflammatory compounds.

In this work, we have built a common binding model of the 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one derivatives into the human neutrophil elastase binding site. This was accomplished through a comparative conformational analysis (using OMEGA, HYPERCHEM, and MOPAC software) of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one inhibitors followed by rigid and flexible molecular docking (by the FRED and GLIDE programs) into the target protein. We conclude that OMEGA software generates the most representative conformers to model the protein-ligand interactions.

Keywords: Conformational analysis, Benzoxazinone derivative, Biologically active conformation, Human neutrophil elastase inhibitor, Molecular docking, serine proteinase, chymotrypsin family, anti-inflammatory compounds, 2-pyridin-3-yl-benzo[d][1, 3]oxazin-4-one derivatives, MOPAC software