Polypharmacological Drug Design Guided by Integrating Phenotypic and Restricted Fragment Docking Strategies

Polypharmacological drugs are of great value for treating
complex
human diseases by the combinative modulation of several biological
targets. However, multitarget drug design with more than two targets
is challenging and generally discovered by serendipity. Herein, a
restricted fragment docking (RFD) computational method combined with
a phenotypic discovery approach was developed for rational polypharmacological
drug design. Via genetic and drug combination studies in a microglial
phenotype, we first identified novel synergistic effects by triple
target modulation toward RIPK1, MAP4K4, and ALK. Drawing on the RFD
method to explore virtual chemical spaces in three target pockets,
we identified a lead compound, LP-10d, that precisely
modulated RIPK1/MAP4K4/ALK for synergistic microglial protection with
low nanomolar potency. LP-10d showed polypharmacology
against multiple neuropathologies in the 3xTg Alzheimer’s disease
mouse model. Our study revealed a potential application of the RFD
method, which is valuable to further polypharmacological drug discovery
involved in clinical studies for treating complex human diseases.

多靶点药物（Polypharmacological drugs）可通过对多个生物靶点的协同调控，用于治疗复杂人类疾病，具有重要应用价值。然而，针对两个以上靶点的多靶点药物设计极具挑战性，其发现通常依赖于偶然契机。为此，本研究开发了一种结合表型发现策略的限制性片段对接（restricted fragment docking, RFD）计算方法，用于合理化多靶点药物设计。通过针对小胶质细胞表型的遗传学与药物组合研究，本研究首次发现了同时靶向RIPK1、MAP4K4与ALK三个靶点的协同调控效应。借助RFD方法探索三个靶点口袋的虚拟化学空间，我们筛选得到先导化合物LP-10d，该化合物可精准调控RIPK1/MAP4K4/ALK靶点，以纳摩尔级的强效活性实现协同性小胶质细胞保护作用。LP-10d在3xTg阿尔茨海默病小鼠模型中展现出针对多种神经病理特征的多靶点药理活性。本研究证实了RFD方法的潜在应用价值，该方法可为后续面向复杂人类疾病的临床研究相关多靶点药物研发提供有力支撑。