Computational Study of Nocardiotide-A Analogues in the Development of Technetium-99m Radiopeptides for Cancer Imaging for Targeting Somatostatin Receptor 2


  • Rizky Juwita Sugiharti School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia
  • Rani Maharani Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jatinangor 45363, Indonesia
  • Rahmana Emran Kartasasmita School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia
  • Daryono Hadi Tjahjono School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia



molecular docking, nocardiotide-A, radiopeptide, 99mTc, SSTR2


Nocardiotide-A (cWIWLVA) is a cyclic peptide with significant cytotoxicity against several cancer cells. The present research aimed to design a radiopeptide based on nocardiotide-A analogues to be labeled by technetium-99m targeting SSTR2, which is the most widely expressed receptor in several types of human cancers and used as radiopeptide target. Nocardiotide-A analogues were individually designed by replacing valine at the lead compound with lysine, arginine, histidine, asparagine, and glutamine, and this was simulated by molecular dynamics using AMBER18. A molecular docking using AutoDock 4.2 was performed and evaluated to understand the effect of chelation of technetium-99m on 99mTc-HYNIC-EDDA and 99mTc-HYNIC-tricine on the binding affinity of nocardiotide-A analogues. The molecular dynamics simulation confirmed that the designed nocardiotide-A-based peptides were stable in the binding pocket of SSTR2 for 200 ns. Moreover, the nocardiotide-A-based radiopeptides are able to interact with residues Q102, D122, Q126, and N276 by building hydrogen bonds, which are essential binding residues in SSTR2. The molecular docking simulation revealed that the best docking parameter is exhibited by 99mTc/EDDA/HYNIC-cWIWLNA and 99mTc/tricine/HYNIC-cWIWLNA with a binding free energy of ?12.59 kcal/mol and ?8.96 kcal/mol, respectively. Taken together, nocardiotide-A-based radiopeptides are prospective to be further developed for cancer imaging targeting SSTR2.


Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A. & Bray, F., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA: a Cancer J. Clin., 71(3), pp. 209-249, 2021.

Eberle, A.N. & Mild, G., Receptor-Mediated Tumor Targeting with Radiopeptides Part 1. General Principles and Methods, J. Recept. Signal Transduct., 29(1), pp. 1-37, 2009.

Reubi, J.C., Peptide Receptors As Molecular Targets for Cancer Diagnosis and Therapy, Endocr. Rev., 24(4), pp. 389-427, 2003.

Jamous, M., Haberkorn, U. & Mier, W., Synthesis of Peptide Radiopharmaceuticals for the Therapy and Diagnosis of Tumor Diseases, Molecules, 18(3), pp. 3379-3409, 2013.

Csaba, Z., Peineau, S. & Dournaud, P., Molecular Mechanisms of Somatostatin Receptor Trafficking, J. Mol. Endocrinol., 48(1), pp. R1-12, 2012.

Hoppenz, P., Els-Heindl, S. & Beck-Sickinger, A.G., Peptide-Drug Conjugates and Their Targets in Advanced Cancer Therapies, Front. in Chem., 8, 571, pp. 1-24, 2020.

Ibrahim, A.H., Attia, E.Z., Hajjar, D., Anany, M.A., Desoukey, S.Y., Fouad, M.A., ... & Abdelmohsen, New Cytotoxic Cyclic Peptide from the Marine Sponge-Associated Nocardiopsis Sp. Ur67, Mar. Drugs, 16(9), 290, pp. 1-13, 2018.

Muhajir, M.I., Hardianto, A., Al?Anshori, J., Sumiarsa, D., Mayanti, T., Nurlelasari, ... & Maharani, R., Total Synthesis of Nocardiotide A by Using a Combination of Solid- and Solution-Phase Methods, Chemistry Select, 6(45), pp. 12941-12946, 2021.

Mikulov M.B. & Miku?, P., Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging And Diagnostics, Pharmaceuticals, 14(2), pp. 1-42, 2021.

Rezazadeh, F. & Sadeghzadeh, N., Tumor Targeting With 99m Tc Radiolabeled Peptides: Clinical Application and Recent Development, Chem. Biol. Drug Des., 93(3), pp. 205-221, 2019.

Zhou, C., Guo, L., Morriello, G., Pasternak, A., Pan, Y., Rohrer, S. P., ... & Yang, L., Nipecotic and Iso-Nipecotic Amides As Potent and Selective Somatostatin Subtype-2 Receptor Agonists, Bioorganic Med. Chem. Lett., 11(3), pp. 415-417, 2001.

Contour-Galca, M.O., Sidhu, A., Plas, P. & Roubert, P., 3-Thio-1,2,4-Triazoles, Novel Somatostatin Sst2/Sst5 Agonists, Bioorganic Med. Chem. Lett., 15(15), pp. 3555-3559, 2005.

Nagarajan, S.K., Babu, S., Sohn, H., Devaraju, P. & Madhavan, T., Toward A Better Understanding of the Interaction Between Somatostatin Receptor 2 and Its Ligands: A Structural Characterization Study Using Molecular Dynamics and Conceptual Density Functional Theory, J. Biomol. Struct. Dyn., 37(12), pp. 3081-3102, 2019.

Borrelli, A., Tornesello, A.L., Tornesello, M.L. & Buonaguro, F.M., Cell Penetrating Peptides As Molecular Carriers for Anti-Cancer Agents, Molecules, 23(2), 2018.

Chiangjong, W., Chutipongtanate, S. & Hongeng, S., Anticancer Peptide: Physicochemical Property, Functional Aspect and Trend In Clinical Application (Review), Int. J. Oncol., 57(3), pp. 678-696, 2020.

Luan, X., Wu, Y., Shen, Y.W., Zhang, H., Zhou, Y.D., Chen, H.Z., ... & Zhang, W.D., Cytotoxic and Antitumor Peptides As Novel Chemotherapeutics, Nat. Prod. Rep., 38(1), pp. 7-17, 2021.

Fani, M., Maecke, H.R. & Okarvi, S.M., Radiolabeled Peptides : Valuable Tools for the Detection and Treatment of Cancer, Theranostics, 2(5), 481, 2012.

Muhammed, M.T. & Aki?Yalcin, E., Homology Modeling In Drug Discovery: Overview, Current Applications, And Future Perspectives, Chem. Biol. Drug Des., 93(1), pp. 12-20, 2019.

Haddad, Y., Adam, V. & Heger, Z., Ten Quick Tips for Homology Modeling of High-Resolution Protein 3D Structures, PLoS Comput. Biol., 16(4), pp. 1-19, 2020.

Bolzati, C., Carta, D., Salvarese, N. & Refosco, F., Chelating Systems for 99mTc/188Re in the Development of Radiolabeled Peptide Pharmaceuticals, Anticancer. Agents Med. Chem., 12(5), pp. 428-461, 2012.

Kaupmann, K., Bruns, C., Raulf, F., Weber, H.P., Mattes, H. & Lbert, H., Two Amino Acids, Located in Transmembrane Domains VI and VII, Determine the Selectivity of the Peptide Agonist SMS 201-995 For the SSTR2 Somatostatin Receptor, The EMBO J., 14(4), pp. 727-735, 1995.

Strnad, J. & Hadcock, J.R., Identification of A Critical Aspartate Residue in Transmembrane Domain Three Necessary For the Binding of Somatostatin to the Somatostatin Receptor SSTR2, Biochemical and Biophysical Research Communications, 216(3). pp. 913-921, 1995.

Liapakis, G., Fitzpatrick, D., Hoeger, C., Rivier, J., Vandlen, R. & Reisine, T., Identification of Ligand Binding Determinants in the Somatostatin Receptor Subtypes 1 And 2, J. Biol. Chem., 271(34), pp. 20331-20339, 1996.