Discovery of novel Cdc25 phosphatase inhibitors with micromolar activity based on the structure-based virtual screening.
Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy because of the correlation of their overexpression with a wide variety of cancers. We have been able to identify five novel Cdc25 phosphatase inhibitors with micromolar activity by means of a computer-aided drug design protocol involving the homology modeling of Cdc25A and the virtual screening with the automated AutoDock program implementing the effects of ligand solvation in the scoring function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC 50 values lower than 10 microM, they can be considered for further development by structure-activity relationship studies or de novo design methods. The differences in binding modes of the identified inhibitors in the active sites of Cdc25A and B are discussed in detail.
Park
Hwangseo
H
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Korea. hspark@sejong.ac.kr
Bahn
Young Jae
YJ
Jung
Suk-Kyeong
SK
Jeong
Dae Gwin
DG
Lee
Sang-Hyeup
SH
Seo
Il
I
Yoon
Tae-Sung
TS
Kim
Seung Jun
SJ
Ryu
Seong Eon
SE
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D020687:cdc25 Phosphatases