In silico molecular docking of IDH1 r132 mutant inhibitors as anti-cancer agents: a comparative study

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. In humans, IDHs exist in three isoforms: IDH1, IDH2 and IDH3. IDH1 and IDH2 use nicotinamide adenine dinucleotide phosphate (NADP+) as a co-factor and function as homodimers. IDH1 is mutated in various types of human cancer such as adult acute myeloid leukemia (AML) and glioma , and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Almost all of the IDH1 mutations occur at codon R132. Its inhibition can suppress or even stop the cancer cells proliferation. Several IDH1 R132 mutant inhibitors have been designed to date. Comparing binding energies of the inhibitors provides a relatively good insight of what is the most effective structure and where is the best region of action. molecular docking was performed by using AutoDockTools-1.5.6 on the inhibitors including AG-881(vorasidenib),BAY-1436032, GSK-321, IDH-305, IDH-889, ML-309, AG-120(Ivosidenib) and AGI-5198. The binding energies of the inhibitors were -2.63, -7.95, -10.34, -5.49, -7.18, -3.17, -2.55 and -3.36, respectively. Inhibitors that attach to the allosteric pocket (AG-881(vorasidenib), BAY-1436032, GSK-321, IDH-305, IDH-889) generally have better binding energies than those which bind to the active site (ML-309, AG-120(Ivosidenib), AG-5198). Also, among these inhibitors, GSK-321 was the best inhibitor in term of binding energy. Result may be used to design and develop anti- IDH1 inhibitors in the future.

کلیدواژه ها:

Isocitrate dehydrogenase (IDH) ، Molecular docking ، R132 Mutation ، Inhibition ، Binding energy