Huo Shuanghong, Wang Junmei, Cieplak Piotr, Kollman Peter A, Kuntz Irwin D
Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0446, USA.
J Med Chem. 2002 Mar 28;45(7):1412-9. doi: 10.1021/jm010338j.
In this study, we compare the calculated and experimental binding free energies for a combinatorial library of inhibitors of cathepsin D (CatD), an aspartyl protease. Using a molecular dynamics (MD)-based, continuum solvent method (MM-PBSA), we are able to reproduce the experimental binding affinity for a set of seven inhibitors with an average error of ca. 1 kcal/mol and a correlation coefficient of 0.98. By comparing the dynamical conformations of the inhibitors complexed with CatD with the initial conformations generated by CombiBuild (University of California, San Francisco, CA, 1995), we have found that the docking conformation observed in an X-ray structure of one peptide inhibitor bound to CatD (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6796-6800) is in good agreement with our MD simulation. However, the DOCK scoring function, based on intermolecular van der Waals and electrostatics, using a distance-dependent dielectric constant (J. Comput. Chem. 1992, 13, 505-524), poorly reproduces the trend of experimental binding affinity for these inhibitors. Finally, the use of PROFEC (J. Comput.-Aided Mol. Des. 1998, 12, 215-227) analysis allowed us to identify two possible substitutions to improve the binding of one of the better inhibitors to CatD. This study offers hope that current methods of estimating the free energy of binding are accurate enough to be used in a multistep virtual screening protocol.
在本研究中，我们比较了组织蛋白酶D（CatD，一种天冬氨酸蛋白酶）抑制剂组合文库的计算结合自由能与实验结合自由能。使用基于分子动力学（MD）的连续介质溶剂方法（MM-PBSA），我们能够重现一组七种抑制剂的实验结合亲和力，平均误差约为1 kcal/mol，相关系数为0.98。通过将与CatD复合的抑制剂的动态构象与CombiBuild（加利福尼亚大学旧金山分校，1995年）生成的初始构象进行比较，我们发现一种与CatD结合的肽抑制剂的X射线结构中观察到的对接构象与我们的MD模拟结果高度吻合。然而，基于分子间范德华力和静电作用、使用距离依赖性介电常数的DOCK评分函数（《计算化学杂志》，1992年，13卷，505 - 524页），对这些抑制剂的实验结合亲和力趋势的重现效果较差。最后，使用PROFEC分析（《计算机辅助分子设计杂志》，1998年，12卷，215 - 227页）使我们能够确定两个可能的取代基，以改善一种较好的抑制剂与CatD的结合。这项研究带来了希望，即当前估计结合自由能的方法足够准确，可用于多步虚拟筛选方案。
