In silico identification and biochemical validation of plausible molecular targets of 4-thiazolidinone derivative Les-3833 as a potential anticancer agent

Synthetic 4-thiazolidinone derivatives have a broad range of pharmacologic activities. Thus, 4-thiazolidinones are being investigated to create new molecules and develop active pharmaceutical substances for anticancer treatment. In our previous study, we investigated the pyrazoline-thiazolidinone-isatin conjugates, and determined that Les-3833 was the most active compound and might act through inhibition of PARP-, MAPK-, JNK-, Bcl-2-, CDK1/cyclin B, and/or the caspase family. The aim of this research was to perform molecular docking studies to enable the construction of a pharmacophore model for the Les-3833 compound and investigate probable biological targets. Pharmacophore modeling software packages performed molecular docking studies of probable biological targets and enabled the construction of a pharmacophore model. Docking models of Les-3833 with 11 enzymes involved in apoptotic mechanisms were studied. Based on the pharmacophore modeling results for all 11 enzymes, Les-3833 is predicted to be most active in Chk‑1, caspase-6, and caspase-8. Immunoblot analysis proved that the application of Les-3833 led to inhibition of Ser345 phosphorylation, which is induced by etoposide, the most important modification responsible for Chk‑1 activity. Taken together with the results of the docking studies, several mechanisms for the expression of antitumor activity by 4-thiazolidinones are suggested, and such multi-affinity is a characteristic feature of all these derivatives. The docking analysis confirmed the affinity of test compound Les-3833 for a topoisomerase II inhibitor and a high possibility of inhibitory interaction with Chk-1, caspase-6, and caspase-8