Abstract
A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.
Highlights
Nowadays, in accordance with more and more mechanisms of diseases being identified [1,2,3,4,5,6], there are increasing numbers of potential target proteins against each disease, which are useful for drug design [7,8,9,10,11]
It indicates that the binding domain in the crystallography structure of target protein will be suitable for docking simulation as the residues in the binding domain have no significant variation
Root-mean-square deviation (RMSD) value between crystallized structure and docking pose of AGI-6780 is 0.3683 A (Figure 2), which indicates that the docking simulation by LigandFit protocol is suitable for virtual screening with IDH2 R140Q mutant proteins
Summary
In accordance with more and more mechanisms of diseases being identified [1,2,3,4,5,6], there are increasing numbers of potential target proteins against each disease, which are useful for drug design [7,8,9,10,11]. Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes affecting point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172, occur frequently in many cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia [14,15,16,17,18,19,20,21,22]. The inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells. A recent research of mutant IDH2 protein shows a compound, AGI-6780, which can inhibit the tumor-associated mutant
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