6PL1

TRK-A IN COMPLEX WITH LIGAND 1B

6PL1 の概要

• エントリーDOI: 10.2210/pdb6pl1/pdb
• 分子名称: High affinity nerve growth factor receptor, N-(5-{[(7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-yl)-N'-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• 機能のキーワード: trk-a kinase domain high affinity nerve growth factor receptor, transferase
• 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: 35921.22

構造登録者

Subramanian, G. (登録日: 2019-06-30, 公開日: 2019-10-09, 最終更新日: 2024-10-23)

主引用文献

Subramanian, G.,Zhu, Y.,Bowen, S.J.,Roush, N.,White, J.A.,Huczek, D.,Zachary, T.,Javens, C.,Williams, T.,Janssen, A.,Gonzales, A.
Lead identification and characterization of hTrkA type 2 inhibitors.
Bioorg.Med.Chem.Lett., 29:126680-126680, 2019

PubMed Abstract: Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.

PubMed: 31610943
DOI: 10.1016/j.bmcl.2019.126680

実験手法

X-RAY DIFFRACTION (2.03 Å)