title: Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors.
abstract: The discovery of selective cyclooxygenase-2 (COX-2) inhibitors represents a major achievement of the efforts over the past few decades to develop therapeutic treatments for inflammation. To gain insights into designing new COX-2-selective inhibitors, we address the energetic and structural basis for the selective inhibition of COX isozymes by means of a combined computational protocol involving docking experiment, force field design for the heme prothetic group, and free energy perturbation (FEP) simulation. We consider both COX-2- and COX-1-selective inhibitors taking the V523I mutant of COX-2 to be a relevant structural model for COX-1 as confirmed by a variety of experimental and theoretical evidences. For all COX-2-selective inhibitors under consideration, we find that free energies of binding become less favorable as the receptor changes from COX-2 to COX-1, due to the weakening and/or loss of hydrogen bond and hydrophobic interactions that stabilize the inhibitors in the COX-2 active site. On the other hand, COX-1-selective oxicam inhibitors gain extra stabilization energy with the change of residue 523 from valine to isoleucine because of the formations of new hydrogen bonds in the enzyme-inhibitor complexes. The utility of the combined computational approach, as a valuable tool for in silico screening of COX-2-selective inhibitors, is further exemplified by identifying the physicochemical origins of the enantiospecific selective inhibition of COX-2 by alpha-substituted indomethacin ethanolamide inhibitors.
authors.affiliation: School of Chemistry and Molecular Engineering, and Center for Molecular Catalysis, Seoul National University, Seoul 151-747, South Korea. hwangseo@snu.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Sangyoub
authors.initials: S
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000187:drug effects*; D012756:Sheep
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases