Perez M A S, Fernandes P A, Ramos M J
REQUIMTE, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.
J Mol Graph Model. 2007 Oct;26(3):634-42. doi: 10.1016/j.jmgm.2007.03.009. Epub 2007 Mar 24.
Nelfinavir (Viracept) is a potent, non-peptidic inhibitor of HIV-1 Protease, which has been marketed for the treatment of HIV infected patients. However, HIV-1 develops drug-resistance which decreases the affinity of Nelfinavir for the binding pocket of Protease. We present here three new variants of Nelfinavir, which we have designed with computational tools, with greater affinity for HIV-1 Protease than Nelfinavir itself. Accordingly, we have introduced rational modifications in Nelfinavir, optimizing its affinity to the most conserved amino acids in Protease, in order to increase the efficiency of the three new inhibitors. Minimization and molecular dynamics simulations have been carried out on four complexes, HIV-1 Protease with Nelfinavir and subsequently with the new inhibitors, respectively, in order to analyze the behavior of the systems. Additionally, we have calculated the binding free energy differences Protease:inhibitor, which gave us a quantitative idea of the new molecules inhibitory efficiency in silico.
奈非那韦（Viracept）是一种强效的非肽类HIV-1蛋白酶抑制剂，已上市用于治疗HIV感染患者。然而，HIV-1会产生耐药性，这会降低奈非那韦对蛋白酶结合口袋的亲和力。我们在此展示了三种新的奈非那韦变体，它们是我们利用计算工具设计的，对HIV-1蛋白酶的亲和力比奈非那韦本身更高。因此，我们对奈非那韦进行了合理修饰，优化其与蛋白酶中最保守氨基酸的亲和力，以提高这三种新抑制剂的效率。分别对四种复合物进行了最小化和分子动力学模拟，即HIV-1蛋白酶与奈非那韦以及随后与新抑制剂的复合物，以分析系统的行为。此外，我们计算了蛋白酶：抑制剂的结合自由能差异，这让我们在计算机模拟中对新分子的抑制效率有了定量的认识。
