7SVP

Structure of compound 34 bound to human Phospholipase D2 catalytic domain

7SVP の概要

• エントリーDOI: 10.2210/pdb7svp/pdb
• 分子名称: Phospholipase D2, 1-(1-{(2S)-1-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-oxopropan-2-yl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (3 entities in total)
• 機能のキーワード: phosphodiesterase, hkd motif, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 292929.14

構造登録者

Metrick, C.M.,Chodaparambil, J.V. (登録日: 2021-11-19, 公開日: 2023-01-25, 最終更新日: 2023-10-25)

主引用文献

May-Dracka, T.L.,Gao, F.,Hopkins, B.T.,Hronowski, X.,Chen, T.,Chodaparambil, J.V.,Metrick, C.M.,Cullivan, M.,Enyedy, I.,Kaliszczak, M.,Kankel, M.W.,Marx, I.,Michell-Robinson, M.A.,Murugan, P.,Kumar, P.R.,Rooney, M.,Schuman, E.,Sen, A.,Wang, T.,Ye, T.,Peterson, E.A.
Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.
Acs Med.Chem.Lett., 13:665-673, 2022

PubMed Abstract: Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for studies. To capture the measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.

PubMed: 35450377
DOI: 10.1021/acsmedchemlett.1c00682

実験手法

X-RAY DIFFRACTION (2.9 Å)