Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis

Dane Huang, Chao Zhao, Ruyue Li, Bingyi Chen, Yuting Zhang, Zhejun Sun, Junkang Wei, Huihao Zhou (), Qiong Gu () and Jun Xu ()
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Dane Huang: Sun Yat-Sen University
Chao Zhao: Sun Yat-Sen University
Ruyue Li: Guangdong Provincial Second Hospital of Traditional Chinese Medicine (Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine)
Bingyi Chen: Sun Yat-Sen University
Yuting Zhang: Sun Yat-Sen University
Zhejun Sun: Sun Yat-Sen University
Junkang Wei: Sun Yat-Sen University
Huihao Zhou: Sun Yat-Sen University
Qiong Gu: Sun Yat-Sen University
Jun Xu: Sun Yat-Sen University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract One of the major challenges for discovering protein-protein interaction inhibitors is identifying selective and druggable binding sites at the protein surface. Here, we report an approach to identify a small molecular binding site to selectively inhibit the interaction of soluble RANKL and RANK for designing anti-osteoporosis drugs without undesirable immunosuppressive effects. Through molecular dynamic simulations, we discovered a binding site that allows a small molecule to selectively interrupt soluble RANKL-RANK interaction and without interfering with the membrane RANKL-RANK interaction. We describe a highly potent inhibitor, S3-15, and demonstrate its specificity to inhibit the soluble RANKL-RANK interaction with in vitro and in vivo studies. S3-15 exhibits anti-osteoporotic effects without causing immunosuppression. Through in silico and in vitro experiments we further confirm the binding model of S3-15 and soluble RANKL. This work might inspire structure-based drug discovery for targeting protein-protein interactions.

Date: 2022
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DOI: 10.1038/s41467-022-33006-4

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