The design of inhibitors for medicinally relevant metalloproteins.
A number of metalloproteins are important medicinal targets for conditions ranging from pathogenic infections to cancer. Many but not all of these metalloproteins contain a zinc(II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In this review several metalloproteins of interest are discussed, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs), anthrax lethal factor (LF), and others. Different strategies that have been employed to design effective inhibitors against these proteins are described, with an effort to highlight the strengths and drawbacks of each approach. An emphasis is placed on examining the bioinorganic chemistry of these metal active sites and how a better understanding of the coordination chemistry in these systems may lead to improved inhibitors. It is hoped that this review will help inspire medicinal, biological, and inorganic chemists to tackle this important problem by considering all aspects of metalloprotein inhibitor design.
Jacobsen
Faith E
FE
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA.
Lewis
Jana A
JA
Cohen
Seth M
SM
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis; D002478:Cells, Cultured; D015195:Drug Design; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008667:Metalloproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D061965:Matrix Metalloproteinase Inhibitors; D008667:Metalloproteins; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases; D015032:Zinc