Abstract
Pyruvate dehydrogenase kinase 3 (PDK3) is a multifunctional enzyme that plays a central role in the cancer metabolic switch by blocking pyruvate catabolism in the TCA cycle. PDK3 plays a significant role in the TCA cycle and cancer cell progression, thus, considered as a novel drug target for developing effective therapeutics against varying types of cancer. Here, we employed a structure-based virtual high-throughput screening of natural compounds from the ZINC database to identify potential inhibitors of PDK3. First, the resulted hits were selected on the basis of their physicochemical and ADMET properties. Further, PAINS filter, binding affinities based on the docking analysis and interaction analysis was carried out to find safe and better hits against PDK3. Finally, we identified four natural compounds bearing admirable affinity towards PDK3. Selected compounds showed appreciable drug-like properties and preferentially interact to the residues of the ATP-binding pocket of PDK3. Binding and structural annotations made in docking analysis were supplemented by all-atom molecular dynamics simulations to evaluate the conformational dynamics, stability and interaction mechanism of PDK3 in complex with one of the identified compounds ZINC08764476. PDK3 and ZINC08764476 forming a stable complex throughout the simulation trajectory. We suggest that compound ZINC08764476 may be exploited as a promising scaffold for the development of potential inhibitors of PDK3 to combat cancer and associated diseases. Communicated by Ramaswamy H. Sarma