META-TYROSINE CONJUGATES LABELED 64CU AND 68GA AS A CANCER RADIODIAGNOSIS AGENT USING MOLECULAR DOCKING SIMULATION ON LAT-1

HOLIS ABDUL HOLIK; ANGELA ELYSIA ELAINE; BERNAP DWI PUTRA SITINJAK; FAISAL MAULANA IBRAHIM; ARIFUDIN ACHMAD; B. S. ARI SUDARMANTO; HARYONO; ACHMAD HUSSEIN SUNDAWA KARTAMIHARDJA

doi:10.22159/ijap.2023.v15s2.30

Authors

HOLIS ABDUL HOLIK Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia. Research Collaboration Center for Theranostic Radiopharmaceuticals, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia https://orcid.org/0000-0002-1303-8812
ANGELA ELYSIA ELAINE Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia
BERNAP DWI PUTRA SITINJAK Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia
FAISAL MAULANA IBRAHIM Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia
ARIFUDIN ACHMAD Department of Nuclear Medicine, Faculty of Medicine/Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia
B. S. ARI SUDARMANTO Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta-55281, Yogyakarta, Indonesia
HARYONO Department of Chemistry, Faculty of Life Sciences, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia
ACHMAD HUSSEIN SUNDAWA KARTAMIHARDJA Department of Nuclear Medicine, Faculty of Medicine/Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia

DOI:

https://doi.org/10.22159/ijap.2023.v15s2.30

Keywords:

Cancer, Radiopharmaceuticals, LAT-1, Meta-tyrosine, Molecular docking

Abstract

Objective: This in silico study aims to determine the most potential compound of meta-tyrosine (JX-075, JX-078, and JX-119) ⁶⁴Cu and ⁶⁸Ga conjugated with various bifunctional chelating agents, NOTA, DOTA, and NODAGA, against the antiporter site of the LAT1 as conduct to develop a cancer diagnostic compound.

Methods: Molecular docking simulation was performed to investigate the interactions between meta-tyrosine compounds and LAT-1. Ligand compounds were drawn in 2D structures using ChemDraw Professional 16.0 and then labeled with ⁶⁴Cu and ⁶⁸Ga to build a radiopharmaceutical scaffold. The docking process was validated, characterized, and evaluated the interaction using several docking protocols in MOE 2020, a license owned by Gadjah Mada University. A visualization of the protein with the ligand was carried out on the BIOVIA Discovery Studio 2020.

Results: Docking simulation results show that JX119 has greater potential due to lower bond energy, JX119_NODAGA_⁶⁸Ga of-9.22 kcal/mol and JX119_NODAGA_⁶⁴Cu of-9.09 kcal/mol. This compound showed interactions with transporter amino acid sites Tyr259 and Phe252, both JX-119_NODAGA ⁶⁸Ga and JX119_NODAGA_⁶⁴Cu.

Conclusion: The compounds [⁶⁴Cu]Cu-NODAGA-JX119 and [⁶⁸Ga]Ga-NODAGA-JX119 are the most potential compounds with the lowest (most negative) Gibbs energy as conduct to develop a diagnostic compound.

Downloads

Download data is not yet available.

References

Bray F, Laversanne M, Weiderpass E, Soerjomataram I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer. 2021;127(16):3029-30.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.

Smith RA, Andrews KS, Brooks D, Fedewa SA, Manassaram Baptiste D, Saslow D. Cancer screening in the United States, 2019: a review of current American Cancer Society guidelines and current issues in cancer screening. CA A Cancer J Clinicians. 2019;69(3):184-210. doi: 10.3322/caac.21557.

Yeong CH, Cheng M, Ng KH. Therapeutic radionuclides in nuclear medicine: current and future prospects. J Zhejiang Univ Sci B. 2014;15(10):845-63. doi: 10.1631/jzus.B1400131.

Huttunen KM, Gynther M, Huttunen J, Puris E, Spicer JA, Denny WA. A selective and slowly reversible inhibitor of l-type amino acid transporter 1 (LAT1) potentiates antiproliferative drug efficacy in cancer cells. J Med Chem. 2016;59(12):5740-51. doi: 10.1021/acs.jmedchem.6b00190.

Häfliger P, Charles RP. The L-type amino acid transporter LAT1-an emerging target in cancer. Int J Mol Sci. 2019;20(10):2428. doi: 10.3390/ijms20102428.

Oda K, Hosoda N, Endo H, Saito K, Tsujihara K, Yamamura M. l-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci. 2010;101(1):173-9. doi: 10.1111/j.1349-7006.2009.01386.x.

Singh N, Ecker G. Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, LAT1. Int J Mol Sci. 2018;19(5):1278. doi: 10.3390/ijms19051278.

Yan R, Li Y, Muller J, Zhang Y, Singer S, Xia L. Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell Discov. 2021;7(1):16. doi: 10.1038/s41421-021-00247-4.

Sgouros G, Bodei L, McDevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020;19(9):589-608. doi: 10.1038/s41573-020-0073-9.

Knapp FF, Dash A. Radiopharmaceuticals for therapy. Berlin: Springer India; 2016.

Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev. 2010;110(5):2858-902. doi: 10.1021/cr900325h.

Alnajjar R, Mostafa A, Kandeil A, Al-Karmalawy AA. Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease. Heliyon. 2020;6(12):e05641. doi: 10.1016/j.6(12):e05641.

Ramirez D, Caballero J. Is it reliable to take the molecular docking top-scoring position as the best solution without considering available structural data? Molecules. 2018;23(5):1038. doi: 10.3390/molecules23051038.

Afriza D, Suriyah WH, Ichwan SJA. In silico analysis of molecular interactions between the anti-apoptotic protein survivin and dentatin, nordentatin, and quercetin. In: Journal of physics. Vol. 1073. IOP Publishing; 2018. p. 032001.

Popovic M. Formulas for death and life: chemical composition and biothermodynamic properties of monkeypox (MPV, MPXV, HMPXV) and vaccinia (VACV) viruses. Therm Sci. 2022;26:4855-68. doi: 10.2298/TSCI220524142P.

Napolitano L, Galluccio M, Scalise M, Parravicini C, Palazzolo L, Eberini I. Novel insights into the transport mechanism of the human amino acid transporter LAT1 (SLC7A5). Probing critical residues for substrate translocation. Biochim Biophys Acta (BBA) Gen Subj. 2017;1861(4):727-36. doi: 10.1016/j.bbagen.2017.01.013.

Pogorelov v T. Protein-ligand docking with MOE: introduction; 2011.

Alghamdi HA, Attique SA, Yan W, Arooj A, Albulym O, Zhu D. Repurposing the inhibitors of COVID-19 key proteins through molecular docking approach. Process Biochem. 2021;110:216-22. doi: 10.1016/j.procbio.2021.08.015.

Attique S, Hassan M, Usman M, Atif R, Mahboob S, Al-Ghanim K. A molecular docking approach to evaluate the pharmacological properties of natural and synthetic treatment candidates for use against hypertension. Int J Environ Res Public Health. 2019;16(6):923.

Vilar S, Cozza G, Moro S. Medicinal chemistry and the molecular operating environment (MOE): application of QSAR and molecular docking to drug discovery. Curr Top Med Chem. 2008;8(18):1555-72.

Ye WL, Shen C, Xiong GL, Ding JJ, Lu AP, Hou TJ. Improving docking-based virtual screening ability by integrating multiple energy auxiliary terms from molecular docking scoring. J Chem Inf Model. 2020;60(9):4216-30.

Maffucci I, Contini A. Explicit ligand hydration shells improve the correlation between MM-PB/GBSA binding energies and experimental activities. J Chem Theory Comput. 2013;9(6):2706-17. doi: 10.1021/ct400045d.

Satpati D, Sharma R, Sarma HD, Dash A. Comparative evaluation of 68Ga-labeled NODAGA, DOTAGA, and HBED-CC-conjugated cNGR peptide chelates as tumor-targeted molecular imaging probes. Chem Biol Drug Des. 2018;91(3):781-8.