Rational drug design applied to myeloperoxidase inhibition

Abstract

Rational drug design is a general approach using protein-structure technique in which the discovery of a ligand can be driven either by chance, screening, or rational theory. Myeloperoxidase (MPO) was rapidly identified as a therapeutical target because of its involvement in chronic inflammatory syndromes. In this context, the research of MPO inhibitors was intensified and development of new chemical entities was rationally driven by the research of ligands that enter into the MPO catalytic pocket. Actually, as soon as crystallography data of MPO have become available and its structure was virtually designed, the rational drug design has been applied to this peroxidase. Pharmaceutical industries and academic laboratories apply rational drug design on MPO by either optimizing known inhibitors or searching new molecules by high-throughput virtual screening. By these ways, they were able to find efficient MPO inhibitors and understand their interactions with the enzyme. During this quest of MPO inhibition, it appears that Glu268 is a crucial residue in order to optimize ligand–target interaction. This amino acid should be carefully considered by medicinal chemist when they design inhibitors interfering with MPO activity.

Keywords::

• medicinal chemistry
• inflammatory disease
• antioxidants

Acknowledgments

Authors would like to thank Prof. Dr. Martine Prevost, Dr. Nicole Moguilevsky, Prof. Dr. Jean Nève, Prof. Dr. Michel Vanhaeverbeek, Prof. Dr. François Dufrasne, IyasAldib, Dr. Jalal Soubhye, Alexandre Rousseau and Dr. Cedric Delporte for their contributions, all these years, on the MPO inhibition researches.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.