In silico identification of small molecules as novel LXR agonists for the treatment of cardiovascular disease and cancer

Original Paper


Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported. To find compounds that are potentially capable of activating LXR, we utilized a high-throughput screening method to search the MolMall database for suitable compounds. Seven candidates with lower GB/SA Hawkins scores than the reference ligand T0901317 were identified. Based on the results of molecular dynamics (MD) simulations, binding free energy analysis, and an analysis of the agonism mechanism, ZINC90512020 and ZINC3845032 were predicted to have high affinities for LXR and high relative stabilization, and were therefore selected as potential LXR agonists. Both of these compounds will undergo further development with a view to utilizing them for the treatment of LXR-related cardiovascular diseases or cancers.


LXR agonists Molecular docking Virtual screening MD simulation MM-PBSA 



We are grateful to our colleagues for their critical reviews and constructive suggestions regarding this manuscript. This work was supported in part by grants from the National Natural Science Foundation of China (nos. 81373311, 31300674, 81173093, 30970643, and J1103518)

Supplementary material

894_2018_3578_Fig5_ESM.gif (248 kb)
Fig. S1

Backbone RMSDs from the second MD simulations of the LXR–ligand complexes. (GIF 248 kb)

894_2018_3578_MOESM1_ESM.tif (1.3 mb)
High-resolution image (TIFF 1329 kb)
894_2018_3578_Fig6_ESM.gif (224 kb)
Fig. S2

Backbone RMSDs from the third MD simulations of the LXR–ligand complexes. (GIF 224 kb)

894_2018_3578_MOESM2_ESM.tif (1.2 mb)
High-resolution image (TIFF 1260 kb)
894_2018_3578_Fig7_ESM.gif (52 kb)
Fig. S3

RMSF profiles for the protein backbones of the LXR–ligand complexes based on the last 10 ns (20–30 ns) of the second MD simulation of each complex. (GIF 52 kb)

894_2018_3578_MOESM3_ESM.tif (425 kb)
High resolution image (TIFF 424 kb)
894_2018_3578_Fig8_ESM.gif (51 kb)
Fig. S4

RMSF profiles for the protein backbones of the LXR–ligand complexes based on the last 10 ns (20–30 ns) of the third MD simulation of each complex (GIF 51 kb)

894_2018_3578_MOESM4_ESM.tif (423 kb)
High-resolution image (TIFF 422 kb)
894_2018_3578_MOESM5_ESM.docx (26 kb)
Table S1 (DOCX 26 kb)
894_2018_3578_MOESM6_ESM.doc (92 kb)
Table S2 (DOC 92 kb)
894_2018_3578_MOESM7_ESM.doc (38 kb)
Table S3 (DOC 37 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life SciencesSichuan UniversityChengduPeople’s Republic of China

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