5G2B

Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-008

5G2B の概要

• エントリーDOI: 10.2210/pdb5g2b/pdb
• 分子名称: CLASS 1 PHOSPHODIESTERASE PDEB1, ZINC ION, MAGNESIUM ION, ... (8 entities in total)
• 機能のキーワード: parasitic pde, african trypanosomiasis, sleeping sickness, hydrolase
• 由来する生物種: TRYPANOSOMA BRUCEI
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82890.77

構造登録者

Singh, A.K.,Anthonyrajah, E.S.,Brown, D.G. (登録日: 2016-04-07, 公開日: 2017-11-29, 最終更新日: 2024-01-10)

主引用文献

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

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: 29672041
DOI: 10.1021/acs.jmedchem.7b01670

実験手法

X-RAY DIFFRACTION (1.83 Å)