The development of molecular clamps as drugs

Some enzymes catalyze the modification of an ensemble of substrates in vivo and, as a consequence, are not ideal targets for active-site-directed drugs. One solution to inhibiting such multisubstrate enzymes would be a drug that binds tightly to only one substrate, which prevents the binding of that substrate to the enzyme. Ideally, such a drug (called a molecular clamp, a molecular forcep or a molecular tweezer) would prevent the enzymatic processing of only the targeted substrate. This would enable the enzyme to function normally on all other substrates. Here, we review the unique steady-state kinetic features of molecular clamp inhibition, identify potential targets for molecular clamp inhibition, and discuss problems for the therapeutic use of molecular clamps.