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Explaining RANKL inhibition by OPG through quantum biochemistry computations and insights into peptide-design for the treatment of osteoporosis

机译：解释OPG通过量子生物化学计算和洞察力设计的RANKL抑制作用，用于治疗骨质疏松症

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Osteoporosis is a degenerative disease associated with excessive bone resorption, a natural process performed by osteoclasts. In turn, osteoclast maturation is critically regulated by the receptor activator of nuclear factor kB ligand (RANKL), its signalling receptor (RANK), and its decoy receptor osteoprotegerin (OPG). The critical role of the protein triad, RANK-RANKL-OPG, in osteoclastogenesis has made their binding an important target for the rational development of drugs against osteoporosis. Based on this, we have performed a quantum biochemistry investigation of the binding between RANKL and its decoy receptor, OPG, in order to analyse the individual contributions of all amino acid residues involved in the complex formation, providing a deeper understanding of the inhibition process. The role of specific residues in the RANKL-OPG binding was evaluated through quantum biochemistry computations performed within the molecular fractionation with conjugate caps (MFCC) methodology, and inter-residue binding energies were calculated within the framework of density functional theory (DFT). Our simulations, considering water effects (implicit and explicit) and the role of the dielectric constant background, attested the major importance of site II, when compared to site I, over OPG binding and functionality, mainly through interactions performed by the tripeptide OPG core, I94-E95-F96. The obtained results also explain (i) the impact of a specific OPG mutation (F96L) on Paget's disease development; (ii) how some pioneers proposed that peptides efficiently inhibit the RANKL-OPG complex, acting as promising drugs for the treatment of osteoporosis. In conclusion, our quantum biochemistry approach provides a solid base that allows important insights into peptide and drug design for the treatment of osteoporosis based on RANKL-OPG binding inhibition.
机译：骨质疏松症是一种与过度骨吸收相关的退行性疾病，其由骨壳组织进行的自然过程。反过来，破骨细胞成熟是由核因子Kb配体（RANKL）的受体激活剂，其信号传导受体（等级）和其诱饵受体骨盆素（OPG）的受体激活剂批判性。蛋白质三合会，Rankl-opg，骨髓细胞发生的统称作用使其对抗骨质疏松症的理性发育的重要靶标。基于此，我们已经对Rankl及其诱饵受体之间的结合进行了量化生物化学研究，以分析复杂形成中涉及的所有氨基酸残基的个体贡献，为抑制过程深入了解。通过在用缀合物帽（MFCC）方法的分子分馏内的量子生物化学计算评估特定残基在RANKL-OPG结合中的作用，并在密度函数理论（DFT）的框架内计算残余物互补能量。我们的模拟，考虑到水效应（隐含和显式）和介电恒定背景的作用，证明了站点II的主要重要性，与现场I相比，过度绑定和功能，主要是通过三肽OPG核心所执行的相互作用， I94-E95-F96。所获得的结果还解释（i）特定OPG突变（F96L）对Paget疾病发展的影响; （ii）一些先驱者提出的是肽有效地抑制RANKL-OPG复合物，作为对骨质疏松症治疗的有希望的药物。总之，我们的量子生物化学方法提供了一种坚实的基础，允许基于RANKL-OP结合抑制治疗骨质疏松症的肽和药物设计的重要见解。

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  • 来源
    《RSC Advances》 |2016年第88期|共17页
  • 作者

    Sousa Bruno L.; Barroso-Neto Ito L.; Oliveira Evanildo F.; Fonseca Emerson; Lima-Neto Pedro; Ladeira Luiz O.; Freire Valder N.;

  • 作者单位

    Univ Fed Ceara Dept Fis BR-60455760 Fortaleza Ceara Brazil;

    Univ Fed Ceara Dept Quim Anal &

    Fis Quim BR-60455760 Fortaleza Ceara Brazil;

    Univ Fed Ceara Dept Fis BR-60455760 Fortaleza Ceara Brazil;

    Univ Fed Minas Gerais Dept Fis Belo Horizonte MG Brazil;

    Univ Fed Ceara Dept Quim Anal &

    Fis Quim BR-60455760 Fortaleza Ceara Brazil;

    Univ Fed Minas Gerais Dept Fis Belo Horizonte MG Brazil;

    Univ Fed Ceara Dept Fis BR-60455760 Fortaleza Ceara Brazil;

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  • 中图分类 化学;
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