6ftw

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Crystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-048

Structural highlights

6ftw is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:E6Z, EDO, EPE, MG, ZN
Gene:PDE4D, DPDE3 (HUMAN)
Activity:3',5'-cyclic-AMP phosphodiesterase, with EC number 3.1.4.53
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PDE4D_HUMAN] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:614613]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.[1]

Function

[PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.[2] [3]

Publication Abstract from PubMed

Several 3',5'-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors.,de Heuvel E, Singh AK, Edink E, van der Meer T, van der Woude M, Sadek P, Krell-Jorgensen MP, van den Bergh T, Veerman J, Caljon G, Kalejaiye TD, Wijtmans M, Maes L, de Koning HP, Jan Sterk G, Siderius M, de Esch IJP, Brown DG, Leurs R Bioorg Med Chem. 2019 Jun 18. pii: S0968-0896(18)31629-8. doi:, 10.1016/j.bmc.2019.06.027. PMID:31327675[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet. 2012 Apr 6;90(4):740-5. doi: 10.1016/j.ajhg.2012.03.003. Epub, 2012 Mar 29. PMID:22464250 doi:10.1016/j.ajhg.2012.03.003
  2. ↑ Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004 Jul 23;15(2):279-86. PMID:15260978 doi:http://dx.doi.org/10.1016/j.molcel.2004.07.005
  3. ↑ Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47. PMID:15576036 doi:http://dx.doi.org/10.1016/j.str.2004.10.004
  4. ↑ de Heuvel E, Singh AK, Edink E, van der Meer T, van der Woude M, Sadek P, Krell-Jorgensen MP, van den Bergh T, Veerman J, Caljon G, Kalejaiye TD, Wijtmans M, Maes L, de Koning HP, Jan Sterk G, Siderius M, de Esch IJP, Brown DG, Leurs R. Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. Bioorg Med Chem. 2019 Jun 18. pii: S0968-0896(18)31629-8. doi:, 10.1016/j.bmc.2019.06.027. PMID:31327675 doi:http://dx.doi.org/10.1016/j.bmc.2019.06.027

Contents


PDB ID 6ftw

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