Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Sep 7:13:982375.
doi: 10.3389/fphar.2022.982375. eCollection 2022.

Discovery of novel IDH1-R132C inhibitors through structure-based virtual screening

Chujiao Hu  1   2   3   4   5 , Zhirui Zeng  4   5 , Dan Ma  3   6 , Zhixin Yin  7 , Shanshan Zhao  7 , Tengxiang Chen  4   5 , Lei Tang  2   3 , Shi Zuo  1   5
Affiliations

Discovery of novel IDH1-R132C inhibitors through structure-based virtual screening

Chujiao Hu et al. Front Pharmacol. .

Abstract

Isocitrate dehydrogenase (IDH) 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 IDH1-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 IDH1-R132C mutation proliferation by > 50%. The compound (T001-0657) showed the most potent effect against cancer cells harboring the IDH1-R132C mutation with a half-maximal inhibitory concentration (IC50) value of 1.311 μM. It also showed a cytotoxic effect against cancer cells with wild-type IDH1 and normal cells with IC50 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 IDH1-R132C. Root-mean-square deviation, root-mean-square fluctuation, and binding free energy calculations showed that both compounds bind tightly to IDH1-R132C. In conclusion, the compound identified in this study had high selectivity for cancer cells harboring IDH1-R132C mutation and could be considered a promising hit compound for further development of IDH1-R132C inhibitors.

Keywords: IDH1-R132C inhibitor; molecular docking; molecular dynamics simulation; tricarboxylic acid cycle (TCA cycle); virtual screening.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Identification of potential IDH1-R132C inhibitors. (A) Flowchart of the hit discovery using docking-based virtual screening to discover of IDH1-R132C inhibitors. (B) The corresponding inhibition rate of 46 molecules at 10 μM in the HT1080 cells.
FIGURE 2
FIGURE 2
Chemical structures of the positive compound and five candidate compounds after preliminary cellular evaluation. (Error bars are mean ± S.D. for three replicates).
FIGURE 3
FIGURE 3
T001-0657 suppresses IDH1 activity in vitro. (A) T001-0657 inhibits the HT1080 cell proliferation, with an IC50 value of 1.311 μM. (B) T001-0657 inhibits the proliferation of U87 cells with an IC50 value of 49.041 μM. (C) Normal cells were exposed to various concentrations of T001-0657 for 48 h to determine the cytotoxic activity. (Each point represents the mean ± standard deviation of the three replicates). Significance: *, p < 0.05; **, p < 0.01.
FIGURE 4
FIGURE 4
The binding pocket of compound A and T001-0657 for IDH1-R132C. (A) Overall figures of the binding of compound A and T001-0657 to IDH1-R132C. Compound A is depicted as red sticks and T001-0657 is depicted as blue sticks. The IDH1-R132C is displayed in cartoon mode (PDB ID 6IO0). (B,C) A close-up view of the key interactions stabilizing compound A/T001-0657 in the IDH1-R132C binding pocket. Compound A/T001-0657 is depicted as red/blue sticks, the surrounding key residues are shown as green sticks and labeled. The hydrogen bonds are shown as a yellow dashed line. (D,E) Two-dimensional binding mode diagram of compound A and T001-0657 with IDH1-R132C; the red solid line indicates the salt-bridge interaction, the green dashed line indicates the π-π stacking interaction, and the black dashed line indicates the hydrogen bonding interaction.
FIGURE 5
FIGURE 5
Stability of the IDH1 inhibitor system. (A) Root-mean-square deviation (RMSD) of the backbone atom of IDH1-R132C, the complex formed by IDH1-R132C with compound A and the heavy atom of compound A. (B)The RMSD of the backbone atom of IDH1-R132C, the complex formed by IDH1-R132C with T001-0657 and the heavy atom of T001-0657. (C) The RMSD of the backbone atom of IDH1-R132C, the complex formed by IDH1-R132C with compound A, and the complex formed by IDH1-R132C with T001-0657. (D) The root-mean-square fluctuation of the backbone atom of IDH1-R132C and IDH1-R132C in the complex with compound A and T001-0657. (E) The solvent-accessible surface area analysis of compound A and T001-0657 bound with IDH1-R132C. (F) The mass-weighted radius of gyration.
FIGURE 6
FIGURE 6
Binding free energy and per-residue decomposition studies. (A) A comparison of the specific energy contributions of IDH1-R132C inhibitors bound to key residues. (B) A comparison of the average conformational overlap maps generated by extracting 1,000 frames of conformation from the two complex traces.
See this image and copyright information in PMC

References

    1. Abbas S., Lugthart S., Kavelaars F. G., Schelen A., Koenders J. E., Zeilemaker A., et al. (2010). Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: Prevalence and prognostic value. Blood 116, 2122–2126. 10.1182/blood-2009-11-250878 PubMed Abstract | 10.1182/blood-2009-11-250878 | Google Scholar - DOI - DOI - PubMed
    1. Alhossary A., Handoko S. D., Mu Y., Kwoh C. K. (2015). Fast, accurate, and reliable molecular docking with QuickVina 2. Bioinformatics 31, 2214–2216. 10.1093/bioinformatics/btv082 PubMed Abstract | 10.1093/bioinformatics/btv082 | Google Scholar - DOI - DOI - PubMed
    1. Amary M. F., Bacsi K., Maggiani F., Damato S., Halai D., Berisha F., et al. (2011). IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343. 10.1002/path.2913 PubMed Abstract | 10.1002/path.2913 | Google Scholar - DOI - DOI - PubMed
    1. Amatangelo M. D., Quek L., Shih A., Stein E. M., Roshal M., David M. D., et al. (2017). Enasidenib induces acute myeloid leukemia cell differentiation to PromoteClinical response. Blood 130, 732–741. 10.1182/blood-2017-04-779447 PubMed Abstract | 10.1182/blood-2017-04-779447 | Google Scholar - DOI - DOI - PMC - PubMed
    1. Badur M. G., Muthusamy T., Parker S. J., Ma S., McBrayer S. K., Cordes T., et al. (2018). Oncogenic R132 IDH1 mutations limit NADPH for de novo lipogenesis through (D)2-hydroxyglutarate production in fibrosarcoma sells. Cell Rep. 25, 1018–1026. e4. 10.1016/j.celrep.2018.09.074 PubMed Abstract | 10.1016/j.celrep.2018.09.074 | Google Scholar - DOI - DOI - PMC - PubMed