title: Combinatorial computational method gives new picomolar ligands for a known enzyme.
abstract: Combinatorial small molecule growth algorithm was used to design inhibitors for human carbonic anhydrase II. Two enantiomeric candidate molecules were predicted to bind with high potency (with R isomer binding stronger than S), but in two distinct conformations. The experiments verified that computational predictions concerning the binding affinities and the binding modes were correct for both isomers. The designed R isomer is the best-known inhibitor (K(d) approximately 30 pM) of human carbonic anhydrase II.
authors.affiliation: Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Bartosz A
authors.initials: BA
authors.lastname: Grzybowski
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ishchenko
authors.forename: Chu-Young
authors.initials: CY
authors.lastname: Kim
authors.forename: George
authors.initials: G
authors.lastname: Topalov
authors.forename: Robert
authors.initials: R
authors.lastname: Chapman
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
authors.forename: George M
authors.initials: GM
authors.lastname: Whitesides
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D006801:Humans; D008024:Ligands; D008832:Microchemistry / Q000379:methods; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D008024:Ligands; D024402:Carbonic Anhydrase II