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1QXL

Crystal structure of Adenosine deaminase complexed with FR235380

Summary for 1QXL
Entry DOI10.2210/pdb1qxl/pdb
DescriptorAdenosine deaminase, ZINC ION, 1-((1R)-1-(HYDROXYMETHYL)-3-{6-[(5-PHENYLPENTANOYL)AMINO]-1H-INDOL-1-YL}PROPYL)-1H-IMIDAZOLE-4-CARBOXAMIDE, ... (4 entities in total)
Functional Keywordsbeta barrel, zinc ion, hydrolase
Biological sourceBos taurus (cattle)
Cellular locationCell membrane ; Peripheral membrane protein ; Extracellular side : P56658
Total number of polymer chains1
Total formula weight40865.68
Authors
Kinoshita, T. (deposition date: 2003-09-08, release date: 2004-09-21, Last modification date: 2024-03-13)
Primary citationTerasaka, T.,Kinoshita, T.,Kuno, M.,Seki, N.,Tanaka, K.,Nakanishi, I.
Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors
J.Med.Chem., 47:3730-3743, 2004
Cited by
PubMed Abstract: We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c.
PubMed: 15239652
DOI: 10.1021/jm0306374
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.25 Å)
Structure validation

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