Jiang Yingying, Luo Xiaogang, Zheng Zhanpeng, Wen Shun, Gao Hongwei, Xu Cheng, Jiang Min, Wang Siyuan
College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
Bioorg Chem. 2024 Dec;153:107826. doi: 10.1016/j.bioorg.2024.107826. Epub 2024 Sep 16.
Receptor activator of nuclear factor-κB ligand (RANKL) is considered the principal regulator of osteoclast differentiation. Therefore, strategies interfering with the RANKL-RANK signaling pathway may effectively inhibit osteoclast differentiation and mitigate bone resorption. Consequently, RANKL has become a promising target for new drug design strategies. Despite extensive research on specific drugs and antibodies, only a few have shown efficacy in treating osteoporosis. To address this challenge, we aimed to explore new approaches for designing drugs for osteoporosis. In this study, a 3D quantitative structure-activity relationship (QSAR) pharmacophore model was built for RANKL with reference to known inhibitor IC values. The optimal pharmacophore model was then employed as a 3D query to screen databases for novel lead compounds. The obtained compounds were subjected to ADMET and TOPKAT analyses to predict drug pharmacokinetics and toxicity. Molecular docking and de novo evolution approaches were applied to verify the docking binding affinities of the compounds. Five candidate compounds were subjected to further in vitro analyses to assess their anti-osteoporotic effects, among which compound 4 demonstrated significant inhibitory activity, achieving an inhibitory rate of 92.6 % on osteoclastogenesis at a concentration of 10 μM. Subsequent molecular dynamics (MD) simulations to assess the stability and behavior of compound 4 and its evolved variant, ZINC00059014397_Evo, within the RANKL binding site revealed that the variant is a potential therapeutic agent for targeting osteoclasts. This study offers valuable insights for developing next generation RANKL inhibitors for osteoporosis treatments.
核因子κB受体活化因子配体（RANKL）被认为是破骨细胞分化的主要调节因子。因此，干扰RANKL-RANK信号通路的策略可能有效抑制破骨细胞分化并减轻骨吸收。因此，RANKL已成为新药设计策略中一个有前景的靶点。尽管对特定药物和抗体进行了广泛研究，但只有少数几种在治疗骨质疏松症方面显示出疗效。为应对这一挑战，我们旨在探索设计治疗骨质疏松症药物的新方法。在本研究中，参考已知抑制剂的IC值，为RANKL建立了三维定量构效关系（QSAR）药效团模型。然后将最佳药效团模型用作三维查询，以筛选数据库中的新型先导化合物。对获得的化合物进行ADMET和TOPKAT分析，以预测药物的药代动力学和毒性。应用分子对接和从头进化方法来验证化合物的对接结合亲和力。对五种候选化合物进行进一步的体外分析，以评估它们的抗骨质疏松作用，其中化合物4表现出显著的抑制活性，在浓度为10μM时对破骨细胞生成的抑制率达到92.6%。随后的分子动力学（MD）模拟评估了化合物4及其进化变体ZINC00059014397_Evo在RANKL结合位点内的稳定性和行为，结果表明该变体是一种靶向破骨细胞的潜在治疗剂。本研究为开发用于治疗骨质疏松症的下一代RANKL抑制剂提供了有价值的见解。
