Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.
Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.
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DOI：
10.1021/acs.cgd.7b00236
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发表时间：
2017-05-03
影响因子：
3.8
通讯作者：
Shtukenberg AG
中科院分区：
文献类型：
--
作者：
Poloni LN;Zhu Z;Garcia-Vázquez N;Yu AC;Connors DM;Hu L;Sahota A;Ward MD;Shtukenberg AG
l-胱氨酸肾结石——l-胱氨酸六角形单晶的聚集体——仅在美国就有超过20000人患有此病。目前的治疗方法往往无效，并产生不良的副作用。认识到l-胱氨酸晶体的生长是结石发病的关键步骤，在l-胱氨酸晶体（0001）表面生长的实时原位原子力显微镜和晶体生长各向异性的测量是在31个成员库中提取的预期抑制剂存在的情况下进行的。抑制晶体生长最有效的分子冒充物是l-胱氨酸模拟物（又称分子冒充物），特别是l-胱氨酸二酯和二胺，其动力学分析揭示了与Cabrera-Vermilyea台阶钉钉一致的共同抑制机制。根据动力学数据估计，l-胱氨酸晶体结合抑制剂的量表明，冒名顶替物与{0001}面结合的可能性小于l-胱氨酸溶质分子结合的可能性，而冒名顶替物与{101′0}面结合的可能性与l-胱氨酸分子相当。这些估计得到了计算结合能的证实。总的来说，这些发现确定了分子冒名顶替者和l-胱氨酸晶体扭结位点之间的分子识别和晶体生长抑制的关键结构因素。观察结果与更有效的抑制剂减少小鼠模型中l-胱氨酸结石负担一致，从而阐明了基于分子设计的结石预防策略。l-胱氨酸晶体生长抑制剂的分子识别因素和明确的晶体位点是利用一个有前景的抑制剂库揭示的。观察结果与Cabrera - Vermilyea步骤固定和通过更有效的抑制剂减少小鼠模型中的l-胱氨酸结石负担一致，阐明了基于分子设计的结石预防策略。
l-Cystine kidney stones—aggregates of single crystals of the hexagonal form of l-cystine—afflict more than 20 000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library. The most effective molecular imposters for crystal growth inhibition were l-cystine mimics (aka molecular imposters), particularly l-cystine diesters and diamides, for which a kinetic analysis revealed a common inhibition mechanism consistent with Cabrera–Vermilyea step pinning. The amount of inhibitor incorporated by l-cystine crystals, estimated from kinetic data, suggests that imposter binding to the {0001} face is less probable than binding of l-cystine solute molecules, whereas imposter binding to {101̅0} faces is comparable to that of l-cystine molecules. These estimates were corroborated by computational binding energies. Collectively, these findings identify the key structural factors responsible for molecular recognition between molecular imposters and l-cystine crystal kink sites, and the inhibition of crystal growth. The observations are consistent with the reduction of l-cystine stone burden in mouse models by the more effective inhibitors, thereby articulating a strategy for stone prevention based on molecular design. The factors responsible for molecular recognition by l-cystine crystal growth inhibitors and well-defined crystal sites are revealed using a library of prospective inhibitors. The observations are consistent with Cabrera−Vermilyea step pinning and the reduction of l-cystine stone burden in mouse models by the more effective inhibitors, articulating a strategy for stone prevention based on molecular design.
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DOI：
10.1098/rsta.1951.0006
发表时间：
1951-01-01
影响因子：
--
作者：
BURTON, WK;CABRERA, N;FRANK, FC
通讯作者：
FRANK, FC
影响因子：
1.8
作者：
Königsberger, E;Wang, ZH;Königsberger, LC
通讯作者：
Königsberger, LC
影响因子：
--
作者：
MICHAELS, AS;TAUSCH, FW
通讯作者：
TAUSCH, FW
影响因子：
2.7
作者：
Dolin, DJ;Asplin, JR;Goldfarb, DS
通讯作者：
Goldfarb, DS
影响因子：
7.3
作者：
Hu, Longqin;Yang, Yanhui;Sahota, Amrik
通讯作者：
Sahota, Amrik