Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4001, South Africa.
J Comput Aided Mol Des. 2018 Mar;32(3):459-471. doi: 10.1007/s10822-018-0099-9. Epub 2018 Feb 3.
The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.
人类免疫缺陷病毒 1 型（HIV-1）的天冬氨酸蛋白酶已成为一种关键的抗病毒靶点，在此基础上开发了许多有用的抗逆转录病毒抑制剂。然而，新的 HIV-1 PR 突变似乎增强了药物耐药性，因此，现有的 FDA 批准药物对蛋白酶的活性降低。最近从 C-SA HIV-1 亚型报告了一种突变和插入指定为 L38L↑N↑L PR。本研究采用两层 ONIOM（QM：MM）方法研究了 9 种 HIV PR 抑制剂对该突变体的结合亲和力。计算得到的结合自由能以及实验数据表明，与 C-SA HIV-1 PR 相比，对 L38L↑N↑L PR 的抑制活性降低。这一观察结果表明，插入和突变显著影响 HIV PIs 和/或亲本 PR 的结合亲和力或特征。对于 9 种抑制剂中的 8 种，计算得到的结合自由能与实验得到的结合自由能具有相同的趋势。这项研究的结果表明，ONIOM 方法可以作为一种可靠的计算方法，用于合理化针对特定靶标的先导化合物。使用分子中的原子（AIM）分析讨论了分子间相互作用的性质，即主客体氢键相互作用。还使用自然键轨道分析来确定 QM 区域的 L38L↑N↑L PR 酶和 FDA 批准药物之间的电荷转移程度。AIM 分析表明，QM 区域的 L38L↑N↑L PR 和 FDA 批准药物之间的相互作用是静电主导的，从 NBO 分析计算的键稳定性支持了 AIM 应用的结果。未来的研究将集中于通过在活性口袋中考虑显式水分子来改进计算模型。我们相信，这种方法有可能提供有助于设计更好的 HIV-1 PR 抗病毒药物的信息。
