Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

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• 作者：Xue Zhi Zhao ; David Hymel ; Terrence R. Burke Jr. ; ^{burkete@helix.nih.gov" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Plk1 polo-box domain ; Ligand optimization ; Oxime ligation ; Cryptic binding pocket
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：5009-5012
• 全文大小：1168 K

文摘

By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists.