Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small‐Molecule CD4 Mimetics and HIV‐1 gp120,ChemMedChem

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Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small‐Molecule CD4 Mimetics and HIV‐1 gp120
ChemMedChem ( IF 3.6 ) Pub Date : 2018-02-09 , DOI: 10.1002/cmdc.201700728
Francesca Moraca ₁ , David Rinaldo ₂ , Amos B. Smith ₃ , Cameron F. Abrams ₄

Affiliation

The small‐molecule CD4 mimetics (smCD4mcs) are a class of highly potent HIV‐1 entry inhibitors characterized by a unique structure–activity relationship (SAR). They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water‐filled cavity at the CD4 binding site on the gp120 surface, the so‐called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all led to loss of activity, despite the fact that they are predicted by standard empirical computational approaches to bind equally well, making it difficult to further optimize this region of the compounds to increase binding to gp120. In this study we used quantum mechanical methods to understand the roots of the interactions between region 1 and the F43 cavity. We clearly demonstrate the presence of halogen bond/σ‐hole and dispersion interactions between region 1 and the F43 cavity residues F376–N377, which are not captured by standard molecular mechanics approaches and the role played by the smCD4mc in the F43 cavity desolvation. These findings rationalize why the halogenated region 1 has proven so difficult to move beyond in smCD4mc optimization, in agreement with experimental evidence.

中文翻译：

特定的非共价相互作用决定了埋入配体部分的最佳结构：小分子CD4模拟物和HIV-1 gp120复合物的QM / MM和纯QM建模

小分子CD4模拟物（smCD4mcs）是一类高度有效的HIV-1进入抑制剂，具有独特的结构-活性关系（SAR）。它们共享一个卤代苯环（区域1），该环深深插入gp120表面CD4结合位点上否则充满水的空腔中，即所谓的F43空腔。尽管实际上是通过标准的经验计算方法预测它们均能很好地结合，但远离该卤代苯基基序的区域1的保守修饰均导致活性丧失，这使得难以进一步优化化合物的该区域以增加结合力到gp120。在这项研究中，我们使用量子力学方法来了解区域1和F43腔之间相互作用的根源。我们清楚地证明了区域1与F43空腔残基F376–N377之间没有卤素键/σ-孔和分散相互作用，这是标准分子力学方法无法捕获的，并且smCD4mc在F43空腔去溶剂化中发挥了作用。这些发现合理地解释了为什么卤化区域1已证明在smCD4mc优化中如此难以超越，这与实验证据相符。

更新日期：2018-02-09

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