5L8Y
Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-937
Summary for 5L8Y
| Entry DOI | 10.2210/pdb5l8y/pdb |
| Descriptor | Phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (8 entities in total) |
| Functional Keywords | parasitic pde, african trypanosomiasis, sleeping sickness, hydrolase |
| Biological source | Trypanosoma brucei |
| Total number of polymer chains | 2 |
| Total formula weight | 82195.99 |
| Authors | Singh, A.K.,Anthonyrajah, E.S.,Brown, D.G. (deposition date: 2016-06-08, release date: 2018-03-14, Last modification date: 2024-05-08) |
| Primary citation | Blaazer, A.R.,Singh, A.K.,de Heuvel, E.,Edink, E.,Orrling, K.M.,Veerman, J.J.N.,van den Bergh, T.,Jansen, C.,Balasubramaniam, E.,Mooij, W.J.,Custers, H.,Sijm, M.,Tagoe, D.N.A.,Kalejaiye, T.D.,Munday, J.C.,Tenor, H.,Matheeussen, A.,Wijtmans, M.,Siderius, M.,de Graaf, C.,Maes, L.,de Koning, H.P.,Bailey, D.S.,Sterk, G.J.,de Esch, I.J.P.,Brown, D.G.,Leurs, R. Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity. J. Med. Chem., 61:3870-3888, 2018 Cited by PubMed Abstract: Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( K = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC = 5.5 and 6.7 μM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis. PubMed: 29672041DOI: 10.1021/acs.jmedchem.7b01670 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.14 Å) |
Structure validation
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