title: Host-guest complexes with protein-ligand-like affinities: computational analysis and design.
abstract: It has recently been discovered that guests combining a nonpolar core with cationic substituents bind cucurbit[7]uril (CB[7]) in water with ultrahigh affinities. The present study uses the Mining Minima algorithm to study the physics of these extraordinary associations and to computationally test a new series of CB[7] ligands designed to bind with similarly high affinity. The calculations reproduce key experimental observations regarding the affinities of ferrocene-based guests with CB[7] and beta-cyclodextrin and provide a coherent view of the roles of electrostatics and configurational entropy as determinants of affinity in these systems. The newly designed series of compounds is based on a bicyclo[2.2.2]octane core, which is similar in size and polarity to the ferrocene core of the existing series. Mining Minima predicts that these new compounds will, like the ferrocenes, bind CB[7] with extremely high affinities.
authors.affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850, USA.
authors.forename: Sarvin
authors.initials: S
authors.lastname: Moghaddam
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D000465:Algorithms; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002412:Cations; D019277:Entropy; D005296:Ferrous Compounds / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D008024:Ligands; D000075163:Metallocenes; D009795:Octanes; D011506:Proteins; D055672:Static Electricity; D047392:beta-Cyclodextrins; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D002412:Cations; D005296:Ferrous Compounds; D007093:Imidazoles; D008024:Ligands; D000075163:Metallocenes; D009795:Octanes; D011506:Proteins; D047392:beta-Cyclodextrins; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; C031215:betadex; C004998:ferrocene