Freitas Renato F, Galembeck Sérgio E
Departamento de Química, FFCLRP, Universidade de São Paulo, 14040-901 Ribeirão Preto-SP, Brasil.
J Phys Chem B. 2006 Oct 26;110(42):21287-98. doi: 10.1021/jp063058u.
The non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are an important class of drugs employed in anti-HIV chemotherapy. TIBO compounds, which belong to the NNRTIs class, are potent inhibitors of the HIV-1 reverse transcriptase enzyme (HIV-1 RT). However, mutations in the amino acids present in the active site of these inhibitors limit their clinical use. In this work, the intermolecular interactions taking place between compounds of the TIBO family and Y181 (C181), K101, and Y188 amino acids are investigated. For this purpose the coordinates of three RT crystalline structures complexed with TIBO were taken from PDB database, and were analyzed by means of the B3LYP/6-31+G(d,p) model. The natural bond orbital (NBO) and atoms in molecules (AIM) methods indicate that not only does the Y181C mutation lead to loss of favorable interactions between the TIBO side chains and tyrosine, but it also affects the interaction between the inhibitor and K101 and Y188. Results also revealed that the interaction between TIBO and K101 is stabilized by N-H...O and N-H...S hydrogen bonds. This is the first time that the presence of the latter hydrogen bond (N-H...S) is reported to play an important role in the stabilization of the interaction between TIBO and K101. In addition the NBO and natural population analyses (NPA) indicate that the 8 Cl-TIBO inhibitor presents a more effective interaction with the Y181, K101, and Y188 than that of 9 Cl-TIBO.
HIV-1逆转录酶的非核苷抑制剂（NNRTIs）是抗HIV化疗中使用的一类重要药物。属于NNRTIs类别的替博（TIBO）化合物是HIV-1逆转录酶（HIV-1 RT）的有效抑制剂。然而，这些抑制剂活性位点中氨基酸的突变限制了它们的临床应用。在这项工作中，研究了替博家族化合物与Y181（C181）、K101和Y188氨基酸之间发生的分子间相互作用。为此，从蛋白质数据银行（PDB）数据库获取了与替博复合的三种逆转录酶晶体结构的坐标，并通过B3LYP/6-31+G(d,p)模型进行分析。自然键轨道（NBO）和分子中的原子（AIM）方法表明，不仅Y181C突变导致替博侧链与酪氨酸之间有利相互作用的丧失，而且它还影响抑制剂与K101和Y188之间的相互作用。结果还表明，替博与K101之间的相互作用通过N-H...O和N-H...S氢键得以稳定。这是首次报道后者的氢键（N-H...S）在替博与K101之间相互作用的稳定中起重要作用。此外，NBO和自然布居分析（NPA）表明，8-氯替博抑制剂与Y181、K101和Y188的相互作用比9-氯替博更有效。
