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Pose Filter-Based Ensemble Learning Enables Discovery of Orally Active, Nonsteroidal Farnesoid X Receptor Agonists
journal contribution
posted on 2020-02-25, 18:38 authored by Jie Xia, Zhenyi Wang, Yi Huan, Wenjie Xue, Xing Wang, Yuxi Wang, Zhenming Liu, Jui-Hua Hsieh, Liangren Zhang, Song Wu, Zhufang Shen, Hongmin Zhang, Xiang Simon WangFarnesoid
X receptor (FXR) agonists can reverse dysregulated bile
acid metabolism, and thus, they are potential therapeutics to prevent
and treat nonalcoholic fatty liver disease. The low success rate of
FXR agonists’ R&D and the side effects of clinical candidates
such as obeticholic acid make it urgent to discover new chemotypes.
Unfortunately, structure-based virtual screening (SBVS) that can speed
up drug discovery has rarely been reported with success for FXR, which
was likely hindered by the failure in addressing protein flexibility.
To address this issue, we devised human FXR (hFXR)-specific ensemble
learning models based on pose filters from 24 agonist-bound hFXR crystal
structures and coupled them to traditional SBVS approaches of the
FRED docking plus Chemgauss4 scoring function. It turned out that
the hFXR-specific pose filter ensemble (PFE) was able to improve ligand
enrichment significantly, which rendered 3RUT-based SBVS with its
PFE the ideal approach for FXR agonist discovery. By screening of
the Specs chemical library and in vitro FXR transactivation bioassay,
we identified a new class of FXR agonists with compound XJ034 as the
representative, which would have been missed if the PFE was not coupled.
Following that, we performed in-depth biological studies which demonstrated
that XJ034 resulted in a downtrend of intracellular triglyceride in
vitro, significantly decreased the serum/liver TG in high fat diet-induced
C57BL/6J obese mice, and more importantly, showed metabolic stabilities
in both plasma and liver microsomes. To provide insight into further
structure-based lead optimization, we solved the crystal structure
of hFXR complexed with compound XJ034, uncovering a unique hydrogen
bond between compound XJ034 and residue Y375. The current work highlights
the power of our pose filter-based ensemble learning approach in terms
of scaffold hopping and provides a promising lead compound for further
development.
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compound XJ 034obeticholic acidresidue Y 375.drug discoveryprotein flexibility24 agonist-bound hFXR crystal structuressuccess rateside effectshFXR complexedFXR transactivation bioassaySpecs chemical library3 RUT-based SBVSintracellular triglycerideSBVS approachesliver diseaseChemgauss 4diet-induced C 57BLPFEdysregulated bile acid metabolismligand enrichmentFXR agonist discoveryliver microsomescrystal structurefilter ensembleXJ 034FXR agonistsNonsteroidal Farnesoid X Receptor Agonists Farnesoid X receptorPose Filter-Based Ensemble Learning Enables DiscoveryTGFRED dockingfilter-based ensemblehydrogen bond
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