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Updated: Jun 12, 2025

Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Polypharmacological Drug Design Guided by Integrating Phenotypic and Restricted Fragment Docking Strategies
Shang Li1, Xinxin Li1, Liangliang Ma1
1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Abstract:
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.
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