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Screening using polymorphs for the crystallization of protein-ligand complexes

机译：使用多晶型物筛选蛋白质-配体复合物的结晶

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摘要

An efficient crystallization screening method is important in drug design to yield high resolution crystallographic structures of protein-ligand complexes to understand inhibitor selectivity and potency for various members of an enzyme family. The strategy starts with a single condition for each protein-ligand complex, and more trials encompassing all polymorph crystallization conditions are included later, eventually defaulting to a more extensive screening for difficult cases. The polymorph screening approach relies on an intrinsic positive feedback mechanism. New polymorphs are constantly discovered since certain ligands favor variant lattices. The new best diffracting polymorph is selected for single-conditions testing, ensuring that as more forms are discovered, the resolution of the structures obtained improves. Continual optimization of the conditions for all crystal forms yields new solutions that become increasingly effective in protein-ligand crystallization trials. More polymorphs imply more lattices suitable to accommodate ligands of greater diversity. Wider seeding opportunities combined with optimized enzyme-specific crystallization conditions improves the outcome and accelerates the screening process so that a conventional full-range crystallization screening is only rarely needed. Having tested this approach with a large repertoire of 100 ligands and 4 enzymes, we expect the method to perform equally well on similar drug-discovery projects.
机译：有效的结晶筛选方法在药物设计中很重要，它可以产生蛋白质-配体复合物的高分辨率晶体结构，以了解抑制剂对酶家族中各个成员的选择性和效力。该策略从针对每种蛋白质-配体复合物的单一条件开始，随后包括更多涵盖所有多晶型物结晶条件的试验，最终默认为对困难病例进行更广泛的筛查。多晶型物筛选方法依赖于内在的正反馈机制。由于某些配体偏爱变异晶格，因此不断发现新的多晶型物。选择新的最佳衍射多晶型物进行单条件测试，以确保发现更多形式时，所获得结构的分辨率得以提高。不断优化所有晶体形式的条件，产生了新的解决方案，这些解决方案在蛋白质-配体结晶试验中变得越来越有效。更多的多晶型物意味着更多的晶格适合容纳更大多样性的配体。更大的播种机会与优化的酶特异性结晶条件相结合，可改善结果并加快筛选过程，因此仅很少需要常规的全范围结晶筛选。用100个配体和4种酶的大量库对这种方法进行了测试，我们希望该方法在类似的药物发现项目中表现同样出色。

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