4CKU
Three dimensional structure of plasmepsin II in complex with hydroxyethylamine-based inhibitor
Summary for 4CKU
| Entry DOI | 10.2210/pdb4cku/pdb |
| Descriptor | 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) |
| Functional Keywords | hydrolase, malaria, drug design |
| Biological source | PLASMODIUM FALCIPARUM (MALARIA PARASITE P. FALCIPARUM) |
| Total number of polymer chains | 6 |
| Total formula weight | 225615.15 |
| Authors | Tars, K.,Leitans, J.,Jaudzems, K. (deposition date: 2014-01-08, release date: 2014-06-18, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 24900843DOI: 10.1021/ML4004952 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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