Abstract
Pyruvate dehydrogenase kinase (PDK) can control the catalytic activity of pyruvate decarboxylation oxidation through the mitochondrial PD complex. Additionally, glycolysis is connected to the production of ATP and the tricarboxylic acid cycle. One up-and-coming method for curing metabolic illnesses like heart failure, cancer, and diabetes is by controlling the expression or activity of PDKs. To find possible bioactive inhibitors of pyruvate dehydrogenase kinase 3 (PDK3), we used a structural-based virtual large-scale analysis of bioactive chemical compounds from the FDA-approved database. Using FDA-approved compounds for the analysis leverages existing safety and efficacy data, significantly accelerating the drug repurposing process. This screening process found two naturally occurring substances with strong affinity and specificity for the PDK3 binding site: bagrosin and dehydrocholic acid. Structural-based investigations provided a precise identification of compounds that fit the active site of PDK3, with desirable binding characteristics, optimizing drug-target interactions. Both substances interact with residues on ATP-binding sites of PDK3 preferentially. Additionally, all-atom molecular dynamic (MD) simulations were used to assess the consistency and dynamics of PDK3 interaction with bagrosin and dehydrocholic acid, and the results indicated that both complexes were stable. The findings might be used to develop innovative PDK3 inhibitors that could be used to treat severe illnesses like cancer. Compounds identified from the FDA-approved database are more likely to have known pharmacokinetics and pharmacodynamics profiles, facilitating their transition into clinical trials.