ABSTRACT
Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Models, Molecular , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Binding Sites , Computational Biology , Crystallography, X-Ray , Drug Design , Humans , Protein Conformation , Structure-Activity Relationship , Tacrine/chemistryABSTRACT
Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures, molecular modeling studies formulated the hypothesis of extra interaction sites in the active gorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. The design strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among the compounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfur atom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitors described to date. The novel inhibitors, bearing postulated key features, validated the hypothesis of the presence of extra interaction sites within the hBuChE active site gorge.
Subject(s)
Acridines/chemical synthesis , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Acetylcholinesterase/metabolism , Acridines/chemistry , Acridines/pharmacology , Binding Sites , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Drug Design , Humans , In Vitro Techniques , Ligands , Models, Molecular , Molecular Probes , Structure-Activity RelationshipABSTRACT
A simple multistep synthetic strategy to 4-substituted 1,2,3,4-tetrahydro-beta-carboline and 1,3,4,9-tetrahydro-pyrano[3,4-b]indole derivatives starting from commercially available indole 2-carboxylic acid (5) is described. The final intramolecular Michael addition promoted by catalytic amount of InBr(3) (5-10 mol %) provided the expected polycyclic compounds in excellent yields (up to 97%) both in anhydrous organic and aqueous media.
