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

Author

Listed:
  • Dane Huang

    (Sun Yat-Sen University
    Guangdong Provincial Second Hospital of Traditional Chinese Medicine (Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine))

  • 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)

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.

Suggested Citation

  • Dane Huang & Chao Zhao & Ruyue Li & Bingyi Chen & Yuting Zhang & Zhejun Sun & Junkang Wei & Huihao Zhou & Qiong Gu & Jun Xu, 2022. "Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33006-4
    DOI: 10.1038/s41467-022-33006-4
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    1. D. Holstead Jones & Tomoki Nakashima & Otto H. Sanchez & Ivona Kozieradzki & Svetlana V. Komarova & Ildiko Sarosi & Sean Morony & Evelyn Rubin & Renu Sarao & Carlo V. Hojilla & Vukoslav Komnenovic & Y, 2006. "Regulation of cancer cell migration and bone metastasis by RANKL," Nature, Nature, vol. 440(7084), pages 692-696, March.
    2. Jinhu Xiong & Keisha Cawley & Marilina Piemontese & Yuko Fujiwara & Haibo Zhao & Joseph J. Goellner & Charles A. O’Brien, 2018. "Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    3. Yuki Ikebuchi & Shigeki Aoki & Masashi Honma & Madoka Hayashi & Yasutaka Sugamori & Masud Khan & Yoshiaki Kariya & Genki Kato & Yasuhiko Tabata & Josef M. Penninger & Nobuyuki Udagawa & Kazuhiro Aoki , 2018. "Coupling of bone resorption and formation by RANKL reverse signalling," Nature, Nature, vol. 561(7722), pages 195-200, September.
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