6X4L

PANK3 complex structure with compound PZ-3565

6X4L の概要

• エントリーDOI: 10.2210/pdb6x4l/pdb
• 分子名称: Pantothenate kinase 3, 1-[4-(5-chloropyrazin-2-yl)piperazin-1-yl]-2-[4-(propan-2-yl)phenyl]ethan-1-one, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: pank, substrate, complex, transferase, pantothenate kinase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43174.71

構造登録者

White, S.W.,Yun, M. (登録日: 2020-05-22, 公開日: 2021-11-24, 最終更新日: 2023-10-18)

主引用文献

Sharma, L.K.,Yun, M.K.,Subramanian, C.,Tangallapally, R.,Jackowski, S.,Rock, C.O.,White, S.W.,Lee, R.E.
LipE guided discovery of isopropylphenyl pyridazines as pantothenate kinase modulators.
Bioorg.Med.Chem., 52:116504-116504, 2021

PubMed 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.

PubMed: 34814071
DOI: 10.1016/j.bmc.2021.116504

実験手法

X-RAY DIFFRACTION (2 Å)