Combinatorial computational method gives new picomolar ligands for a known enzyme.
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.
Grzybowski
Bartosz A
BA
Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, USA.
Ishchenko
Alexey V
AV
Kim
Chu-Young
CY
Topalov
George
G
Chapman
Robert
R
Christianson
David W
DW
Whitesides
George M
GM
Shakhnovich
Eugene I
EI
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
D008024:Ligands; D024402:Carbonic Anhydrase II