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,