title: Slow-binding inhibition of cholinesterases, pharmacological and toxicological relevance.
abstract: Slow-binding inhibition (SBI) of enzymes is characterized by slow establishment of enzyme-inhibitor equilibrium. Cholinesterases (ChEs) display slow onset of inhibition with certain inhibitors. After a survey of SBI mechanisms, SBI of ChEs is examined. SBI results either from simple slow interaction, induced-fit, or slow conformational selection. In some cases, the slow equilibrium is followed by an irreversible chemical step. This later was observed for the interaction of ChEs with certain irreversible inhibitors. Because slow-binding inhibitors present pharmacological advantages over classical reversible inhibitors (e.g. long target-residence times, resulting in prolonged efficacy with minimal unwanted side effects), slow-binding inhibitors of ChEs are promising new drugs for treatment of Alzheimer disease, myasthenia, and neuroprotection. SBI is also of toxicological importance; it may play a role in mechanisms of resistance and protection against poisoning by irreversible agents.
authors.affiliation: Laboratory of Neuropharmacology, Kazan Federal University, 18, Kremlyovskaya St., Kazan, 420008, Russia. Electronic address: pym.masson@free.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Masson
authors.affiliation: Laboratory of Computer Modeling of Biomolecular Systems and Nanomaterials, Emanuel Institute of Biochemical Physics of RAS, 4, Kosygina St., Moscow, 119334, Russia. Electronic address: sofya.lushchekina@gmail.com.
authors.forename: Sofya V
authors.initials: SV
authors.lastname: Lushchekina
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D008958:Models, Molecular; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Butyrylcholinesterase; Residence time; Slow-binding inhibition; Tight-binding inhibition