While noncovalent inhibitors associate and dissociate freely from enzymes (depending on binding constant) and thus require sustained concentrations of inhibitor to inactivate an enzyme, (irreversible) covalent inhibitors cannot dissociate ensuring continuous presence of inhibitor. The irreversibility of binding means that binding of the guidance system to the target does not need to be as strong to abrogate activity, and so inhibitors may be smaller and likely less lipophilic and thus (perhaps) more water-soluble. If covalent inhibitors are smaller than traditional noncovalent inhibitors and have longer durations of action, the doses administered can be smaller and less frequent, reducing likely side effects and improving selectivity. In many cases, the separability of reactive groups from guidance systems may make the design of covalent drugs easier. If the strength of initial binding does not need to be as high, an irreversible covalent inhibitor can inhibit enzymes without discrete binding sites such as those involved in protein-protein interactions Finally, because the bonds between irreversible covalent inhibitors and targets do not break, mass spectrometric analysis of binding is facile, making high-throughput screening of inhibition simpler. However, covalent inhibitors can also have liabilities relative to noncovalent drugs. The irreversibility of binding requires that any binding be selective; off-target binding is irreversible and thus likely to be long-lasting. If sufficiently reactive warheads are used, off-target effects are likely.