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