Modeling of Cdc25B Dual Specifity Protein Phosphatase Inhibitors: Docking of Ligands and Enzymatic Inhibition Mechanism

Abstract

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs.

Independent Mechanistic Inhibition of Cdc25 Phosphatases by a Natural Product Caulibugulone

“…Crystallographic data (Reynolds et al, 1999) and molecular modeling studies (Lavecchia et al, 2006) suggest that the active sites in the Cdc25 family members are sufficiently different, suggesting that selectivity among catalytic inhibitors of Cdc25 phosphatases may be possible. Thus, we expanded our previous investigation of caulibugulone inhibition of Cdc25B to examine the selectivity of these compounds against all three human Cdc25 phosphatases.…”

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…13). Active site binding and cysteine-adduction by electrophilic pharmacophores was optimized based on molecular docking studies using the crystal structure of the Cdc25B catalytic domain (124,183,212). It is interesting to note that the napthoquinone menadione (vitamin K 3 ) discussed above in the context of prooxidant redox cycling (Section II.C) represents an early prototype inhibitor of Cdc25 phosphatase enzymatic activity (382).…”

Synthesis and Molecular modeling of some new chalcones derived from coumarine as CDC25 phosphatases inhibitors

“…Compounds 7 and 8 had their binding mode in the opposite direction. Docking could not give the explanation of the inhibitory activity 29,[35][36][37][38][39][40][41][42][43][44][45][46][47] , so it was necessary to synthesize these molecules and evaluated their biological activities with CDC25A and B then verification of their reversibility.…”