Determining the Crystal Structures of Peptide Analogs of Boronic Acid in the Absence of Single Crystals: Intricate Motifs of Ixazomib Citrate Revealed by XRPD Guided by ss-NMR,Crystal Growth & Design

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Determining the Crystal Structures of Peptide Analogs of Boronic Acid in the Absence of Single Crystals: Intricate Motifs of Ixazomib Citrate Revealed by XRPD Guided by ss-NMR
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2018-04-30 00:00:00 , DOI: 10.1021/acs.cgd.8b00402
Michal Hušák ₁ , Alexandr Jegorov ₂ , Jan Rohlíček ₃ , Andrew Fitch ₄ , Jiří Czernek ₅ , Libor Kobera ₅ , Jiří Brus ₅

Affiliation

Uncertainties in the structure determination of peptide analogs of boronic acid, exacerbated by the many coordination modes of boron, represent an obstacle in understanding their role in living organisms and thus also in developing the next generation of anticancer drugs. For that reason, we present here a general experimental-computational strategy allowing structure determination of complex boronic acid derivatives with extensive conformational variability. We demonstrate successful solution of the crystal structures of two nonsolvated polymorphs of ixazomib citrate directly from synchrotron powder diffraction data, which is challenging because the two molecules in the asymmetric unit cell that exhibit 32 degrees of conformational freedom push the limits of current solution procedures. We used a novel two-step Rietveld refinement based on DFT-D restraints to improve information quality derived from powder diffraction data to be comparable with that of single-crystal solutions. NMR crystallography was applied to verify the crystal structures, and the high potential value of using ¹¹B NMR parameters toward the solution of unknown structures was demonstrated. Evolution of ¹¹B–¹¹B double-quantum coherences allows probing of interatomic distances up to 7 Å. Overall, we present an integrated approach that applies several techniques in conjunction to provide otherwise unavailable structural information.

中文翻译：

在没有单晶的情况下确定硼酸肽类似物的晶体结构：柠檬酸依沙单抗的复杂图案由ss-NMR指导的XRPD揭示

硼的许多配位模式加剧了硼酸肽类似物结构确定中的不确定性，这是理解它们在活生物体中的作用并因此在开发下一代抗癌药中的障碍。出于这个原因，我们在这里提出了一种通用的实验计算策略，可以确定具有广泛构象变异性的复杂硼酸衍生物的结构。我们直接从同步加速器粉末衍射数据中成功地证明了柠檬酸埃沙米单抗的两个非溶剂化多晶型物的晶体结构成功解决方案，这是具有挑战性的，因为非对称晶胞中表现出32度构象自由度的两个分子推动了当前溶液法的极限。我们使用了基于DFT-D约束的新颖的两步Rietveld精炼技术，以提高从粉末衍射数据得出的信息质量，使其与单晶溶液的质量相当。核磁共振晶体学用于验证晶体结构，并具有很高的潜在应用价值。证明了朝向未知结构的溶液的¹¹ B NMR参数。的进化¹¹ B- ¹¹乙双量子相干探测允许原子间距离的最多7埃。总体而言，我们提出了一种整合的方法，该方法结合使用了几种技术来提供否则无法获得的结构信息。

更新日期：2018-04-30

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