6X4K

PANK3 complex structure with compound PZ-2890

Summary for 6X4K

• Entry DOI: 10.2210/pdb6x4k/pdb
• Descriptor: Pantothenate kinase 3, 4-(6-cyanopyridazin-3-yl)-N-[4-(propan-2-yl)phenyl]-3,4-dihydropyrazine-1(2H)-carboxamide, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (7 entities in total)
• Functional Keywords: pank, substrate, complex, transferase, pantothenate kinase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43164.24

Authors

White, S.W.,Yun, M. (deposition date: 2020-05-22, release date: 2021-11-24, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)