Filizola M, Perez J J, Palomer A, Mauleón D
Department d'Enginyeria Quimica, Universitat Politecnica de Catalunya, ETS d'Enginyers Industrials, Barcelona, Spain.
J Mol Graph Model. 1997 Oct;15(5):290-300. doi: 10.1016/s1093-3263(97)00107-1.
To understand the structural features that dictate the selectivity of diverse nonsteroidal antiinflammatory drugs for the two isoforms of the human prostaglandin H2 synthase (PGHS), the three-dimensional (3D) structure of human COX-2 was assessed by means of sequence homology modeling. The ovine COX-1 structure, solved by X-ray diffraction methods and sharing a 61% sequence identity with human COX-2, was used as template. Both structures were energy minimized using the AMBER 4.0 force field with a dielectric constant of 4r. (S)-Flurbiprofen, a nonselective COX inhibitor, and SC-558, a COX-2-selective ligand, were docked at the cyclooxygenase binding site in both isozymes, evidencing the role of different residues in the ligand-protein interaction. The 3D structures of the constructed four ligand-enzyme complexes were refined by energy minimization. Molecular dynamics simulations were also carried out, to understand more deeply the structural origins of the selectivity. Distances calculated during the dynamics process between the different ligands and the interacting residues of the two PGHS isozymes provided evidence of the flexible nature of the cyclooxygenase active site, permitting the identification of different conserved and nonconserved residues as responsible for ligand selectivity.
为了解决定多种非甾体抗炎药对人前列腺素H2合酶（PGHS）两种同工型选择性的结构特征，通过序列同源性建模评估了人COX-2的三维（3D）结构。以通过X射线衍射方法解析的、与人类COX-2具有61%序列同一性的绵羊COX-1结构作为模板。使用介电常数为4r的AMBER 4.0力场对两种结构进行能量最小化。将非选择性COX抑制剂（S）-氟比洛芬和COX-2选择性配体SC-558对接至两种同工酶的环氧化酶结合位点，证明了不同残基在配体-蛋白质相互作用中的作用。通过能量最小化对构建的四种配体-酶复合物的3D结构进行优化。还进行了分子动力学模拟，以更深入地了解选择性的结构起源。在动力学过程中计算的不同配体与两种PGHS同工酶相互作用残基之间的距离，证明了环氧化酶活性位点的柔性，从而能够确定不同的保守和非保守残基对配体选择性的作用。
