Inhibition Of Mmp-1 And Mmp-13 With Phosphinic Acids That Exploit Binding In The S-2 Pocket
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS(1999)
摘要
Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S-2 pocket of these enzymes were designed. The synthesis and testing of 2 suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of 2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S-2, S-1', S-2' and S-3', were optimized yielding compounds with low double-digit nM IC50's against these enzymes. (C) 1999 Elsevier Science Ltd. All rights reserved.
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