Polypharmacological\nDrug Design Guided by Integrating\nPhenotypic and Restricted Fragment Docking Strategies

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