Discovery of novel -R132C inhibitors through structure-based virtual screening.

Isocitrate dehydrogenase () belongs to a family of enzymes involved in glycometabolism. It is found in many living organisms and is one of the most mutated metabolic enzymes. In the current study, we identified novel 1-R132C inhibitors using docking-based virtual screening and cellular inhibition assays. A total of 100 molecules with high docking scores were obtained from docking-based virtual screening. The cellular inhibition assay demonstrated five compounds at a concentration of 10 μM could inhibit cancer cells harboring the 1-R132C mutation proliferation by > 50%. The compound (T001-0657) showed the most potent effect against cancer cells harboring the 1-R132C mutation with a half-maximal inhibitory concentration (IC) value of 1.311 μM. It also showed a cytotoxic effect against cancer cells with wild-type 1 and normal cells with IC values of 49.041 μM and >50 μM, respectively. Molecular dynamics simulations were performed to investigate the stability of the kinase structure binding of allosteric inhibitor compound A and the identified compound T001-0657 binds to 1-R132C. Root-mean-square deviation, root-mean-square fluctuation, and binding free energy calculations showed that both compounds bind tightly to 1-R132C. In conclusion, the compound identified in this study had high selectivity for cancer cells harboring 1-R132C mutation and could be considered a promising hit compound for further development of 1-R132C inhibitors.