Chheda Pratik Rajesh, Cooling Grant T, Dean Sondra F, Propp Jonah, Hobbs Kathryn F, Spies M Ashley
Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, Iowa 52242, United States of America.
Department of Biochemistry, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, United States of America.
Commun Chem. 2021;4. doi: 10.1038/s42004-021-00605-z. Epub 2021 Dec 10.
One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target. In the current studies we present a successful way forward in rationally exploiting the cryptic allosteric pocket of glutamate racemase, an essential enzyme in this pathogen's life cycle. A wide range of computational and experimental methods are employed in a workflow leading to the discovery of a series of natural product allosteric inhibitors which occupy the allosteric pocket of this essential racemase. The confluence of these studies reveals a fascinating source of the allosteric inhibition, which centers on the abolition of essential monomer-monomer coupled motion networks.
药物设计中我们面临的最大挑战之一是针对酶靶点中的隐秘变构口袋。在高通量筛选活动中经常会发现确实能与这些隐秘口袋结合的药物先导物，但其作用机制却很少被理解。然而，变构口袋往往为针对特定靶点的药物开发提供了最佳选择。在当前的研究中，我们展示了一条成功的途径，即合理利用谷氨酸消旋酶的隐秘变构口袋，该酶是这种病原体生命周期中的一种必需酶。在一个工作流程中采用了广泛的计算和实验方法，从而发现了一系列占据这种必需消旋酶变构口袋的天然产物变构抑制剂。这些研究的融合揭示了变构抑制的一个引人入胜的来源，其核心是消除必需的单体 - 单体耦合运动网络。
