Structure-based de novo design and biochemical evaluation of novel Cdc25 phosphatase inhibitors.
Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. We have been able to identify 32 novel Cdc25 phosphatase inhibitors with micromolar activity by means of a structure-based de novo design method with the two known inhibitor scaffolds. Because the newly discovered inhibitors are structurally diverse and have desirable physicochemical properties as a drug candidate, they deserve further investigation as anticancer drugs. The differences in binding modes of the identified inhibitors in the active sites of Cdc25A and B are addressed in detail.
Park
Hwangseo
H
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-ku, Seoul 143-747, Republic of Korea. hspark@sejong.ac.kr
Bahn
Young Jae
YJ
Ryu
Seong Eon
SE
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D020687:cdc25 Phosphatases / Q000737:chemistry*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020687:cdc25 Phosphatases