Polypharmacological Drug Design Guided by Integrating Phenotypic and Restricted Fragment Docking Strategies.
Shang LiXinxin LiLiangliang MaZhongwen LuoFucheng YinYonglei ZhangYifan ChenSiyuan WanHan ZhouXiao-Bing WangLing-Yi KongPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- drug discovery
- endothelial cells
- mouse model
- molecular dynamics
- inflammatory response
- molecular dynamics simulations
- induced pluripotent stem cells
- lipopolysaccharide induced
- drug induced
- neuropathic pain
- pluripotent stem cells
- gene expression
- lps induced
- emergency department
- cancer therapy
- high throughput
- spinal cord injury
- protein protein
- climate change
- cognitive decline
- drug delivery
- single cell
- copy number