Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation

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• 作者：Nader N. Nasief^a ; ^b ; ^{nnnasief@yahoo.com} ; Ahmed M. Said^a ; ^c ; David Hangauer^a ; ^{hangauer@buffalo.edu}
• 关键词：Thrombin ; Protein-ligand binding ; Desolvation ; Bioisosterism ; Hydrogen bond ; Cooperativity ; Nonadditivity ; B3LYP/6-31G&lowast
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：5 January 2017
• 年：2017
• 卷：125
• 期：Complete
• 页码：975-991
• 全文大小：1659 K
• 卷排序：125

文摘

The role of H-bond basicity in SAR studies was explored in thrombin inhibitors. H-bond basicity/strength was systematically modulated via bioisosterism. Improved strength of H-bonds to the protein did not improve binding affinity. Decreased strength of H-bonds to water of desolvation lead to better inhibitors. Bioisosteric replacements were found to produce synergism in SAR modifications.