A Comparative Docking Studies of Dichloroacetate Analogues on Four Isozymes of Pyruvate Dehydrogenase Kinase in Humans

Abstract:

Introduction: The four Pyruvate dehydrogenase kinases (PDKs) that regulate the mammalian Pyruvate dehydrogenase complex (PDC) are a novel class of kinases that are expressed in most tissues. PDK is a novel therapeutic target in oncology. Recent studies show that various oncogenes or transcription factors essential for cancer development, such as loss of p53 or activation of HIF1α can induce PDK expression and therefor inhibit PDH and glucose oxidation. Dichloroacetate (DCA) is a pyruvate mimetic anti-cancer compound that stimulatethe activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of PDKs. Methods: In this study, More than 200 DCA analogues were designed. Proper docking protocols were presented for the four isoenzymes of PDK using Autodock 4.2 and Vinasoftwares. Results: The docking binding energy values were in the order of PDK2>PDK1>PDK4>PDK3. ANOVA studies shows that the P value is significant at the level of 0.05 for PDK2 compared to PDK1, PDK2 and PDK3. Conclusion: The results show that the most sensitive to DCA and its analogues was PDK2. The validity of docking procedure was proved by high values of ROC_AUC or EF_max factor.

Key words: DCA analogues, Molecular docking studies, PDK isozymes, Pyruvate dehydrogenase kinase, Statistical analysis.