Designing metalloinhibitors for delivery to peptide receptors in enzymes.
Metalloenzymes are frequently targets for the action of drugs which exert their effects through direct coordination to a metal receptor. The reverse of this principle, the simple new concept of using inhibitors containing metal ions to target peptide receptors in enzymes, is now described. Such "metalloinhibitors" have opportunities for covalent or ionic metal-enzyme interactions which can substantially increase the inhibitor-enzyme binding energy that usually arises from combined ionic, hydrogen-bonding and hydrophobic interactions. Although simple metal salts are known to inhibit numerous enzymes in vitro, no concerted attempts have yet been made to elaborate ligand environments of metals in order to potentiate inhibition, provide enzyme selectivity or protect against compromising in vivo toxicities. Regulation of the ligand microenvironment of the metal can produce spectacular changes in coordinating properties of and ligand affinities for metal ions. Strategies are now proposed for optimising inhibitor-enzyme binding, enhancing selectivity, limiting toxicity and for efficient delivery of this new category of prospective drugs.
Fairlie
D P
DP
Centre for Drug Design & Development, University of Queensland, Brisbane, Australia.
D001665:Binding Sites / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D008667:Metalloproteins / Q000378:metabolism*; D009942:Organometallic Compounds / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018000:Receptors, Peptide / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008667:Metalloproteins; D009942:Organometallic Compounds; D018000:Receptors, Peptide