4CKU

Three dimensional structure of plasmepsin II in complex with hydroxyethylamine-based inhibitor

4CKU の概要

• エントリーDOI: 10.2210/pdb4cku/pdb
• 分子名称: PLASMEPSIN-2, 5-[1,1-bis(oxidanylidene)-1,2-thiazinan-2-yl]-N3-[(2S,3R)-4-[2-(3-methoxyphenyl)propan-2-ylamino]-3-oxidanyl-1-phenyl-butan-2-yl]-N1,N1-dipropyl-benzene-1,3-dicarboxamide (3 entities in total)
• 機能のキーワード: hydrolase, malaria, drug design
• 由来する生物種: PLASMODIUM FALCIPARUM (MALARIA PARASITE P. FALCIPARUM)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 225615.15

構造登録者

Tars, K.,Leitans, J.,Jaudzems, K. (登録日: 2014-01-08, 公開日: 2014-06-18, 最終更新日: 2024-10-23)

主引用文献

Jaudzems, K.,Tars, K.,Maurops, G.,Ivdra, N.,Otikovs, M.,Leitans, J.,Kanepe-Lapsa, I.,Domraceva, I.,Mutule, I.,Trapencieris, P.,Blackman, M.J.,Jirgensons, A.
Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit.
Acs Med.Chem.Lett., 5:373-, 2014

PubMed Abstract: Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

PubMed: 24900843
DOI: 10.1021/ML4004952

実験手法

X-RAY DIFFRACTION (1.85 Å)