Dynamic deconvolution of a pre-equilibrated dynamic combinatorial library of acetylcholinesterase inhibitors

作者：Bunyapaiboonsri T; Ramstrom O; Lohmann S; Lehn JM^*; Peng L; Goeldner M

来源：ChemBioChem, 2001, 2(6): 438-444.

DOI：10.1002/1439-7633(20010601)2:6<438::aid-cbic438>3.0.co;2-j

• acetylcholinesterase
• combinatorial chemistry
• enzyme catalysis
• hydrolases
• inhibitors

A dynamic combinatorial library composed of interconverting acylhydrazones has been generated and screened towards inhibition of acetylcholinesterase from the electric ray Torpedo marmorata. Starting from a small set (13) of initial hydrazide and aldehyde building blocks, a library containing possibly 66 different species was obtained in a single operation. Of all possible acylhydrazones formed, active compounds containing two terminal cationic recognition groups separated by an appropriate distance, permitting two-site binding, could be rapidly identified by using a dynamic deconvolution-screening procedure, based on the sequential removal of starting building blocks. A very potent bis-pyridinium inhibitor (K (i)= 1.09 nM, alphaK(i) = 2.80 nM) was selected from the process and the contribution of various structural features to inhibitory potency was evaluated.

• 出版日期2001-6-1