Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design

Title:Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design

Volume: 17 Issue: 10

Author(s): Jing-Wei Wu, Huan Zhang, Yu-Qing Duan, Wei-Li Dong, Xian-Chao Cheng, Shu-Qing Wang and Run-Ling Wang

Affiliation:

Keywords: ADMET, cancer, Cdc25B inhibitors, de novo design, drug design, molecular dynamics.

Abstract: The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.

Cite this article as:

Wu Jing-Wei, Zhang Huan, Duan Yu-Qing, Dong Wei-Li, Cheng Xian-Chao, Wang Shu-Qing and Wang Run-Ling, Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design, Combinatorial Chemistry & High Throughput Screening 2014; 17 (10) . https://dx.doi.org/10.2174/1386207317666141029223505