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.