Combinatorial computational method gives new picomolar ligands for a known enzyme

Bartosz A. Grzybowski; Alexey V. Ishchenko; Chu Young Kim; George Topalov; Robert Chapman; David W. Christianson; George M. Whitesides; Eugene I. Shakhnovich

doi:10.1073/pnas.032673399

Combinatorial computational method gives new picomolar ligands for a known enzyme

Bartosz A. Grzybowski
, Alexey V. Ishchenko
, Chu Young Kim
, George Topalov
, Robert Chapman
, David W. Christianson
, George M. Whitesides
, Eugene I. Shakhnovich

Research output: Contribution to journal › Article › peer-review

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 ∼ 30 pM) of human carbonic anhydrase II.

Original language	English (US)
Pages (from-to)	1270-1273
Number of pages	4
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	99
Issue number	3
DOIs	https://doi.org/10.1073/pnas.032673399
State	Published - Feb 5 2002
Externally published	Yes

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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 (Kd ∼ 30 pM) of human carbonic anhydrase II.",

author = "Grzybowski, \{Bartosz A.\} and Ishchenko, \{Alexey V.\} and Kim, \{Chu Young\} and George Topalov and Robert Chapman and Christianson, \{David W.\} and Whitesides, \{George M.\} and Shakhnovich, \{Eugene I.\}",

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doi = "10.1073/pnas.032673399",

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T1 - Combinatorial computational method gives new picomolar ligands for a known enzyme

AU - Grzybowski, Bartosz A.

AU - Ishchenko, Alexey V.

AU - Kim, Chu Young

AU - Topalov, George

AU - Chapman, Robert

AU - Christianson, David W.

AU - Whitesides, George M.

AU - Shakhnovich, Eugene I.

PY - 2002/2/5

Y1 - 2002/2/5

N2 - 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 (Kd ∼ 30 pM) of human carbonic anhydrase II.

AB - 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 (Kd ∼ 30 pM) of human carbonic anhydrase II.

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 3

ER -

Combinatorial computational method gives new picomolar ligands for a known enzyme

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