X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.

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Lee KM, Choi WJ, Lee Y, Lee HJ, Zhao LX, Lee HW, Park JG, Kim HO, Hwang KY, Heo YS, Choi S, Jeong LS

X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.

J Med Chem. 2011 Feb 24;54(4):930-8. doi: 10.1021/jm1010836. Epub 2011 Jan 12.

PubMed ID

21226494 [ View in PubMed

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Abstract

The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3'-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4'-CH(2)OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(1'R,2'S)-9-(2-Hydroxy-3'-Keto-Cyclopenten-1-yl)Adenine	Adenosylhomocysteinase	IC 50 (nM)	5830	N/A	N/A	Details