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Drug Design Targeting Protein–Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 Interface

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† Biophysics Graduate Program, The Ohio State University, Columbus, Ohio 43210, United States
‡ Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, United States
§ Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
∥ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
*Phone: 614-247-8786. Fax: 614-292-2435. E-mail: [email protected]
Cite this: J. Med. Chem. 2014, 57, 3, 632–641
Publication Date (Web):January 23, 2014
https://doi.org/10.1021/jm401144z
Copyright © 2014 American Chemical Society
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    Abstract

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    The IL-6/GP130/STAT3 pathway is critical for the progression of multiple types of cancers. We report here the discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 protein–protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into hot spots of GP130 D1 domain by MLSD to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compounds. Similarity searches of virtual hits on drug databases identified raloxifene and bazedoxifene as potential inhibitors of IL-6/GP130 interaction. In cancer cell assays both compounds bind to GP130 and demonstrated selective inhibition of IL-6 induced STAT3 phosphorylation and were significantly more potent than the previously reported natural product inhibitor MDL-A. The identified drugs represent a new class of lead compounds with piperidine, benzothiophene, and indole scaffolds to inhibit IL-6 induced homodimerization of GP130. Besides potential direct usage for clinic trials, the two compounds can also serve as lead compounds for optimization to speed the development of drugs selectively targeting the IL-6/GP130/STAT3 cancer signaling pathway.

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