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LipE 引导发现异丙基苯基哒嗪作为泛酸激酶调节剂。

LipE guided discovery of isopropylphenyl pyridazines as pantothenate kinase modulators.

机构信息

Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas PI, MS1000, Memphis, TN 38105, United States; Department of Infectious Diseases, St. Jude Children's Research Hospital, United States.

Department of Structural Biology, St. Jude Children's Research Hospital, United States.

出版信息

Bioorg Med Chem. 2021 Dec 15;52:116504. doi: 10.1016/j.bmc.2021.116504. Epub 2021 Nov 12.

DOI:10.1016/j.bmc.2021.116504
PMID:34814071
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8693618/
Abstract

Pantothenate kinase (PANK) is the critical regulator of intracellular levels of coenzyme A and has emerged as an attractive target for treating neurological and metabolic disorders. This report describes the optimization, synthesis, and full structure-activity relationships of a new chemical series of pantothenate competitive PANK inhibitors. Potent drug-like molecules were obtained by optimizing a high throughput screening hit, using lipophilic ligand efficiency (LipE) derived from human PANK3 IC values to guide ligand development. X-ray crystal structures of PANK3 with index inhibitors from the optimization were determined to rationalize the emerging structure activity relationships. The analysis revealed a key bidentate hydrogen bonding interaction between pyridazine and R306' as a major contributor to the LipE gain observed in the optimization. A tractable series of PANK3 modulators with nanomolar potency, excellent LipE values, desirable physicochemical properties, and a well-defined structural binding mode was produced from this study.

摘要

泛酸激酶 (PANK) 是辅酶 A 细胞内水平的关键调节剂，已成为治疗神经和代谢紊乱的有吸引力的靶点。本报告描述了一种新型泛酸竞争 PANK 抑制剂的化学系列的优化、合成和完整的结构活性关系。通过优化高通量筛选的命中化合物，使用源自人 PANK3 IC 值的亲脂性配体效率 (LipE) 来指导配体的开发，获得了有效的药物样分子。用优化过程中的抑制剂与 PANK3 的 X 射线晶体结构来合理推断出现的结构活性关系。分析表明，嘧啶嗪和 R306'之间的关键双齿氢键相互作用是优化过程中观察到的 LipE 增益的主要贡献者。从这项研究中产生了一系列具有纳摩尔效力、优异的 LipE 值、理想的物理化学性质和明确的结构结合模式的 PANK3 调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/1f33d58f16ea/nihms-1758667-f0044.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/1eecdfb7d985/nihms-1758667-f0038.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/141d8fb2a063/nihms-1758667-f0039.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/3490742d87d7/nihms-1758667-f0040.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/82d710f3d2a8/nihms-1758667-f0041.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/6875dc8975d5/nihms-1758667-f0042.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/fbb83bbbcfac/nihms-1758667-f0043.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ece/8693618/1f33d58f16ea/nihms-1758667-f0044.jpg

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