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基于结构的药物发现中的蛋白质灵活性和物种特异性:二叶酸减少酶作为测试系统的测试

Anna L Bowman¹, Michael G Lerner, Heather A Carlson

¹Department of Medicinal Chemistry and Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.

Journal of the American Chemical Society

|March 6, 2007

概括

这项研究引入了一种多重蛋白质结构 (MPS) 方法,用于识别特定药物支架,用于像二叶酸还原酶 (DHFR) 等标. 该方法通过提高目标特异性和减少假阳性来增强药物发现.

科学领域:

计算化学是一种计算化学.
结构生物学是结构生物学.
药物发现药物发现

背景情况:

基于结构的药物发现旨在识别针对特定蛋白质标的新型抑制剂.
挑战包括探索广的化学空间,同时保持目标特异性,避免假阳性.

研究的目的:

开发和验证一种方法,用于识别具有高目标特异性的抑制剂的适当化学空间.
将这种方法应用于二叶酸减少酶 (DHFR),以找到特定物种的抑制剂.

主要方法:

使用多个X射线晶体结构扩展了多重蛋白质结构 (MPS) 方法.
为人类和Pneumocystis carinii DHFR.开发了基于受体的药模型.
将蛋白质灵活性纳入模型中.

主要成果:

在MPS模型中,已知DHFR抑制剂对非抑制剂具有很高的选择性.
人类和P. carinii DHFR药模型中的微妙差异确定了特定物种的抑制剂.
基于不太灵活的结构 (Candida albicans DHFR) 的模型表现较差.

结论:

在基于结构的药物发现中,MPS技术是一个有前途的进步,特别是用于识别特定物种的抑制剂.
实现物种特异性对于治疗成功至关重要,特别是针对病原体和人类宿主中的DHFR等酶.
该方法适用于DHFR和其他医学相关的蛋白质.

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