Residence time and more recently the association rate constant k_on are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure–kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant k_on decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.

中文翻译：

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配体去溶剂化率和影响热休克蛋白90（Hsp90）抑制剂的药物停留时间。

停留时间以及最近的缔合速率常数k _on越来越被认为是药物体内功效和安全性的重要参数。但是，由于缺乏如何优化这些参数的知识，限制了它们在药物开发中的广泛考虑。在这项研究中，对一组176种热休克蛋白90抑制剂进行了研究，结合了结构动力学关系，X射线晶体学和分子动力学模拟，以找到如何合理减慢速率的具体方案。我们发现，通过引入极性取代基增加的配体去溶剂化障碍导致了显著ķ_上减少。通过将极性部分引入配体的指向疏水腔的那些部分来实现减慢。我们通过增加三种Hsp90抑制剂的极性来验证该方案，并观察到导通速率的降低9倍，13倍和45倍，并且停留时间延长了9倍。这种延长是由过渡态不稳定而不是基态稳定引起的。