Uncovering the Binding Mode of γ -Secretase Inhibitors

Knowledge of how
transition state inhibitors bind to γ-secretase
is of major importance for the design of new Alzheimer’s disease
therapies. On the basis of the known structure of γ-secretase
in complex with a fragment of the amyloid precursor protein, we generated
a structural model of γ-secretase in complex with the effective
L-685,458 transition state inhibitor. The predicted binding mode is
in excellent agreement with experimental data, mimicking all enzyme–substrate
interactions at the active site and forming the relevant transition
state geometry with the active site aspartate residues. The model
also indicates the possible location and nature of the amino acid
residues forming the proposed binding pockets S1′, S2′,
and S3′ near the active site that are occupied by chemical
groups of the inhibitor. In addition, we found that the stability
of the complex is very likely sensitive to the pH value. Comparative
simulations on the binding of L-685,458 and the epimer L682,679 allowed
us to explain the strongly reduced affinity of the epimer for γ-secretase.
The structural model could form a valuable basis for the design of
new or modified γ-secretase inhibitors.

了解过渡态抑制剂与γ-分泌酶（γ-secretase）的结合方式，对于新型阿尔茨海默病治疗药物的开发具有核心重要性。基于已解析的γ-分泌酶与淀粉样前体蛋白（amyloid precursor protein）片段形成的复合物结构，我们构建了γ-分泌酶与高效L-685,458过渡态抑制剂的复合物结构模型。该预测的结合模式与实验数据高度契合，不仅完美模拟了活性位点处所有酶-底物相互作用，还与活性位点的天冬氨酸残基形成了符合预期的过渡态几何构象。该模型还阐明了活性位点附近S1′、S2′及S3′结合口袋的潜在位置与氨基酸残基组成，这些口袋恰好被抑制剂的化学基团所占据。此外，我们发现该复合物的稳定性极有可能受pH值调控。通过对L-685,458及其差向异构体L682,679的结合过程开展对比模拟，我们阐释了该差向异构体对γ-分泌酶亲和力显著降低的分子机制。本研究得到的结构模型可为新型或修饰型γ-分泌酶抑制剂的开发提供极具价值的理论基础。