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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Structure-thermodynamics-relationships of hepatitis C viral NS3 protease inhibitors
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Structure-thermodynamics-relationships of hepatitis C viral NS3 protease inhibitors

机译：丙型肝炎病毒NS3蛋白酶抑制剂的结构 - 热力学关系

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Thermodynamic parameters were determined for structurally-related inhibitors of HCV NS3 protease to assess how binding entropies and enthalpies vary with incremental changes at the P2 and P3 inhibitor subsites. Changing the heterocyclic substituent at P2 from a pyridyl to a 7-methoxy-2-phenyl-4-quinolyl group leads to a 710-fold increase in affinity. Annelating a benzene ring onto a pyridine ring leads to quinoline-derived inhibitors having higher affinities, but the individual enthalpy and entropy contributions are markedly different for each ligand pair. Introducing a phenyl group at C2 of the heterocyclic ring at P2 uniformly leads to higher affinity analogs with more favorable binding entropies, while adding a methoxy group at C7 of the quinoline ring at P2 provides derivatives with more favorable binding enthalpies. Significant enthalpy/entropy compensation is observed for structural changes made to inhibitors lacking a 2-phenyl substituent, whereas favorable changes in both binding enthalpies and entropies accompany structural modifications when a 2-phenyl group is present. Overall, binding energetics of inhibitors having a 2-phenyl-4-quinolyl group at P2 are dominated by entropic effects, whereas binding of the corresponding norphenyl analogs are primarily enthalpy driven. Notably, the reversal from an entropy driven association to an enthalpy driven one for this set of inhibitors also correlates with alternate binding modes. When the steric bulk of the side chain at P3 is increased from a hydrogen atom to a tert-butyl group, there is a 770-fold improvement in affinity. The 30-fold increase resulting from the first methyl group is solely the consequence of a more favorable change in entropy, whereas subsequent additions of methyl groups leads to modest increases in affinity that arise primarily from incremental improvements in binding enthalpies accompanied with smaller favorable entropic contributions. Crown Copyright (c) 2020 Published by Elsevier Masson SAS. All rights reserved.
机译：测定热力学参数用于HCV NS3蛋白酶的结构相关抑制剂，以评估结合熵和焓如何随P2和P3抑制剂底座的增量变化而变化。将P 2的杂环取代基从吡啶基改变为7-甲氧基-2-苯基-4-喹啉，其亲和力增加710倍。 Annelating苯环到吡啶环导致喹啉衍生的具有更高亲和力的抑制剂，但个别的焓和熵的贡献对每个配体对显着不同。在P2均匀地引入引线在杂环的C2苯基至更高亲和力的类似物与更有利的结合熵，而在喹啉环的C7加入甲氧基在P2提供了更多的有利的结合焓衍生物。观察到对缺乏2-苯基取代基的抑制剂的结构变化观察到显着的焓/熵补偿，而当存在2-苯基时，结合焓和熵伴随的结合焓和熵伴随的变化。总体而言，在P2处具有2-苯基-4-喹啉基的抑制剂的结合能量是通过熵效应的主导，而相应的诺苯基类似物的结合主要是焓驱动的。值得注意的是，从熵驱动的关联与该组抑制剂的焓驱动的逆转的逆转也与交替结合模式相关。当P3处的侧链的侧链从氢原子增加到叔丁基时，亲和力的提高770倍。由第一甲基产生的30倍增加仅是熵更有利的变化的结果，而随后的加入甲基导致适度增加的亲和力主要来自结合焓的增量改善伴随着较小的有利熵贡献。 Crown版权（c）2020由Elsevier Masson SA发布。版权所有。

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