Binding thermodynamics of substituted diaminopyrimidine renin inhibitors
Binding thermodynamics of substituted diaminopyrimidine renin inhibitors
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DOI：
10.1016/j.ab.2006.10.017
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发表时间：
2007-01-01
影响因子：
2.9
通讯作者：
Mochalkin, Igor
中科院分区：
文献类型：
--
作者：
Sarver, Ronald W.;Peevers, Jeanette;Mochalkin, Igor
肾素是一种乙酰化蛋白酶，参与血管紧张素11的产生，血管紧张素11是一种有效的血管收缩剂。肾素抑制剂可以防止血管收缩，因此可以用于治疗高血压。高通量筛选工作确定了一个小分子肾素抑制剂的核心取代二氨基嘧啶环。基于这一线索的并行药物化学工作产生了化合物1。1结合到肾素的复合物结晶，并通过X-射线衍射获得结构数据。该结构表明存在相邻的未被占据的结合口袋。开始进行合成努力以将功能性扩展到这些口袋中，从而提高亲和力并调整药代动力学参数。采用等温滴定量热法，还收集了抑制剂与肾素结合的热力学数据。这些数据被用来帮助指导抑制剂的优化，建议从热力学和结构的角度来提高结合亲和力的分子改变。添加延伸到S3亚口袋中的甲氧基丙基改善了抑制剂亲和力，并导致更大的结合焓。最初添加到嘧啶环模板延伸到大的疏水性S2口袋没有提高亲和力和显着改变的热力学驱动力的结合相互作用。核心模板的结合是热力学驱动的，而初始抑制剂与S2延伸的结合是热力学和熵驱动的，但失去了显着的结合焓。然后将额外的静电相互作用并入S2扩展中以提高结合焓，同时利用有利的熵。(c)2006年爱思唯尔公司All rights reserved.
Renin is an aspartyl protease involved in the production of angiotensin 11, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy. (c) 2006 Elsevier Inc. All rights reserved.