Atypical Protonation States in the Active Site of HIV-1 Protease: A Computational Study

详细信息    查看全文

• 作者：Paul Czodrowski ; Christoph A. Sotriffer ; Gerhard Klebe
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：July 2007
• 年：2007
• 卷：47
• 期：4
• 页码：1590 - 1598
• 全文大小：216K
• 年卷期：v.47,no.4(July 2007)
• ISSN：1549-960X

文摘

The HIV protease (HIVP) is a prominent example for successful structure-based drug design. Besides itspharmaceutical impact, it is a well-studied system for which, as experimentally evidenced, protonation changesin the active site occur upon ligand binding. Therefore, it serves as an ideal candidate for a case study usingour newly developed partial charge model, which was optimized toward the application of Poisson-Boltzmannbased pK_a calculations. The charge model suggests reliably experimentally determined protonation states inthe active site of HIVP. Furthermore, we perform pK_a calculations for two HIVP complexes with noveltypes of inhibitors developed and synthesized in our group. For these complexes, no experimental knowledgeabout the protonation states is given. For one of the compounds, containing a central pyrrolidine ring, thecalculations predict that both catalytic aspartates should be deprotonated upon ligand binding.