1uml
From Proteopedia
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Crystal structure of adenosine deaminase complexed with a potent inhibitor FR233624
Overview
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-bu, tyl]imidazole-4-carboxamide 8c.
About this Structure
1UML is a Single protein structure of sequence from Bos taurus with ZN and FR4 as ligands. Active as Adenosine deaminase, with EC number 3.5.4.4 Full crystallographic information is available from OCA.
Reference
Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors., Terasaka T, Kinoshita T, Kuno M, Seki N, Tanaka K, Nakanishi I, J Med Chem. 2004 Jul 15;47(15):3730-43. PMID:15239652
Page seeded by OCA on Wed Nov 21 04:14:56 2007
Categories: Adenosine deaminase | Bos taurus | Single protein | Kinoshita, T. | FR4 | ZN | Beta barrel | Zinc
