Abstract
Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC50 value of 3.3 μM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.