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结:用于发现代抑制剂的口袋定向片段选

Ashley E Modell¹, Frank Marrone¹, Nihar R Panigrahi¹

¹Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States.

Journal of the American Chemical Society

|January 14, 2022

概括

设计用于蛋白相互作用的强联体可能具有挑战性. 这项研究结合了计算方法和实验选,以优化非自然侧链,增强结合 afinity 改善药物发现.

科学领域:

医学化学
计算生物学
结构生物学

背景情况:

约束是蛋白质表面的有价值的配体,但往往缺乏结合性.
通过结合利用受体表面裂的非自然侧链,可以实现增强结合亲和力.
之前的计算工作 (J. 是的在化学上. 这就是我现在所做的. 2017) 绘制了蛋白质表面,以指导非自然侧链设计.

研究的目的:

优化p300/CBP联合激活剂的KIX域的联体.
为设计作为蛋白质-蛋白质相互作用的抑制剂的类药物制定一个一般框架.
使用计算和实验策略克服结能力的局限性.

主要方法:

使用AlphaSpace计算方法预测针对KIX域的联体.
使用结策略对碎片进行实验选作为非自然侧链.
综合计算预测与实验验证,用于微调非自然侧链.

主要成果:

计算方法显著提高了联体的结合亲和力.
对非自然侧链的实验选对于微调结合力至关重要.
综合方法提供了一种优化体模拟剂的强有力的方法.

结论:

一个协同的计算-实验框架有效地优化了蛋白质-蛋白质相互作用的抑制.
这一策略为开发强效基疗法提供了可通用的方法.
该方法解决了像KIX领域这样的难以实现的强效抑制剂的挑战.

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Protein-protein Interfaces

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