Computer screening of peptidomimetics and small-molecule ligands of B-cell membrane proteins for therapy of Burkitt lymphoma

  • Received 31.07.2023

  • Revised 11.10.2023

  • Accepted 28.11.2023



  • 1,390 Views

  • Retrieved from Vol. 5, No. 4, 2023

  • Pages 25-33

The capabilities of molecular modelling and docking allow for the discovery of new potential drug agents to improve the treatment of diseases, which is a current concern. The objective of this study was to conduct in silico screening for antibody mimetics to B-cell membrane proteins for the treatment of Burkitt lymphoma through virtual screening. In this work, a standard protocol for structure-based virtual screening was employed, with the distinction that pharmacophores for screening were built not based on small-molecule ligands but on selected amino acid residues of antibodies. Based on literature data and the presence of a mechanism of direct cytotoxic action, as well as the availability of 3D structures of complexes, three monoclonal antibodies were selected: obinutuzumab, epratuzumab, and atezolizumab. The identification of biological targets was carried out by searching for 3D structures of selected complexes with target proteins in the Protein Data Bank. For virtual screening, the web service Pharmit was chosen. Using the Molecular Operating Environment program, pharmacophore models were constructed for three complexes: CD20 and obinutuzumab, CD22 and epratuzumab, and PD-L1 and atezolizumab. Docking with the CD20, CD22, and PD-L1 proteins was conducted at the binding sites recognised by the original antibody. Through in silico virtual screening using the Molecular Operating Environment software, a search for antibody mimetics to B-cell membrane proteins for Burkitt lymphoma treatment was conducted, resulting in the selection of 5 potential anti-lymphoma agents: CHEMBL505179 for the CD20 receptor, an antagonist of the melanocortin receptor for CD20 (PubChem-44406884), an inhibitor of blood clotting Factor Xa for CD22 (PubChem-136510605), and a blocker of epithelial Na+ channels for CD22 (PubChem-126761430), and an agonist of the melanocortin receptor for PD-L1 (PubChem-25078192). The obtained results can be applied in the pharmaceutical industry and oncological practice to enhance therapeutic outcomes in the treatment of patients with Burkitt lymphoma

molecular docking; pharmacophores; antibodies; mimetics; immunogenicity

https://doi.org/10.61751/bmbr/4.2023.25

[1] Ai S, Lin G, Bai Y, Liu X, Piao L. QSAR classification-based virtual screening followed by molecular docking identification of potential COX-2 inhibitors in a natural product library. J Comput Biol. 2019;26(11):1296–15. DOI: 10.1089/cmb.2019.0142

[2] Kucherenko L, Brytanova T, Hotsulia A. Synthesis, molecular docking, and ADME analysis of a series of 4-amino-3,5-dimethyl-1,2,4-triazole derivatives. Curr Issues Pharm Med Sci. 2023;16(2):147–53. DOI: 10.14739/2409-2932.2023.2.281039

[3] Zhang Y, Zhang TJ, Tu S, Zhang ZH, Meng FH. Identification of novel Src inhibitors: Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations. Molecules. 2020;25(18):e4094. DOI: 10.3390/molecules25184094

[4] Ren S, Yassar A. Recent research progress in indophenine-based-functional materials: Design, synthesis, and optoelectronic applications. Materials. 2023;16(6):e2474. DOI: 10.3390/ma16062474

[5] Sharma K, Lanzilotto A, Yakubu J, Therkelsen S, Vöegel CD, Du Toit T, et al. Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities. bioRxiv [Internet]. 2023 November 2 [cited 2023 November 7]. DOI: 10.1101/2023.10.31.564977

[6] Lupaescu AV, Mocanu CS, Drochioiu G, Ciobanu CI. Zinc binding to NAP-type neuroprotective peptides: Nuclear magnetic resonance studies and molecular modeling. Pharmaceuticals. 2021;14(10):e1011. DOI: 10.3390/ph14101011

[7] King RL, Hsi ED, Chan WC, Piris MA, Cook JR, Scott DW, Swerdlow SH. Diagnostic approaches and future directions in Burkitt lymphoma and high-grade B-cell lymphoma. Virchows Arch. 2023;482:193–5. DOI: 10.1007/s00428-022-03404-6

[8] Yang X, Huang Q, Li A, Chen Y, Xu W, Li J, et al. A long-term retrospective study on sporadic Burkitt lymphoma in Chinese population. Medicine. 2020;99(5):e18438. DOI: 10.1097/MD.0000000000018438

[9] Villalobo A. Ca2+ signaling and Src functions in tumor cells. Biomolecules. 2023;13(12):e1739. DOI: 10.3390/biom13121739

[10] Lutsenko T, Сhalenko M. The use of monoclonal antibodies in oncotherapy. Proceedings of the International Scientific and Practical Conference “Modern Technologies of Biomedical Engineering”; 2022; Odesa. Odesa, Ukraine: Odesа Polytechnic National University; 2022. P. 49–52.

[11] Nasution MAF, Stephanie F, Tambunan USF. Pharmacophore-based virtual screening and molecular docking simulation of flavonoids as smoothened protein inhibitor of Hedgehog signaling pathways [Internet]. In: Mart T, Triyono D, Anggraningrum IT, editors. Proceedings of the 4th International Symposium on Current Progress in Mathematics and Sciences; 2018 Oct 30-31; Depok. Indonesia: AIP Conference Proceedings; 2019. DOI: 10.1063/1.5132487

[12] Cerqueira NMFS, Gesto D, Oliveira EF, Santos-Martins D, Brás NF, Sousa SF, et al. Receptor-based virtual screening protocol for drug discovery. Arch Biochem Biophys. 2015;582:56–67. DOI: 10.1016/j.abb.2015.05.011

[13] Fu Y, Sun YN, Yi KH, Li MQ, Cao HF, Li JZ, Ye F. Combination of virtual screening protocol by in silico toward the discovery of novel 4-hydroxyphenylpyruvate dioxygenase inhibitors. Front Chem. 2018;6:14. DOI: 10.3389/fchem.2018.00014

[14] Peptidic macrocycles [Internet]. [cited 2023 November 7]. Available from: https://www.asinex.com/peptidomimetics

[15] Sunseri J, Koes DR. Pharmit: Interactive exploration of chemical space. Nucleic Acids Res. 2016;44(1):442–48. DOI: 10.1093%2Fnar%2Fgkw287

[16] Koes DR, Camacho CJ. Pharmer: Efficient and exact pharmacophore search. J Chem Inf Model. 2011;51(6):1307–14. DOI: 10.1021/ci200097m

[17] Kumar A, Planchais C, Fronzes R, Mouquet H, Reyes N. Binding mechanisms of therapeutic antibodies to human CD20. Science. 2020;369(6505):793–99. DOI: 10.1126/science.abb8008

[18] Nasr MR, Rosenthal N, Syrbu S. Expression profiling of transcription factors in B- or T-acute lymphoblastic leukemia/lymphoma and Burkitt lymphoma: Usefulness of PAX5 immunostaining as pan-pre-B-cell marker. Am J Clin Pathol. 2010;133(1):41–48. DOI: 10.1309/ajcpyp00jnufwccy

[19] Horna P, Nowakowski G, Endell J, Boxhammer R. Comparative assessment of surface CD19 and CD20 expression on B-cell lymphomas from clinical biopsies: Implications for targeted therapies. Blood. 2019;134(Suppl 1):e5345. DOI: 10.1182/blood-2019-129600

[20] Weber T, Bötticher B, Mier W, Sauter M, Krämer S, Leotta K, et al. High treatment efficacy by dual targeting of Burkitt’s lymphoma xenografted mice with a177Lu-based CD22-specific radioimmunoconjugate and rituximab. Eur J Nucl Med Mol Imaging. 2016;43(3):489–98. DOI: 10.1007/s00259-015-3175-6

[21] Majzner RG, Simon JS, Grosso JF, Martinez D, Pawel BR, Santi M, et al. Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues. Cancer. 2017;123(19):3807–15. DOI: 10.1002/cncr.30724

[22] Ereño-Orbea J, Sicard T, Cui H, Mazhab-Jafari MT, Benlekbir S, Guarné A, et al. Molecular basis of human CD22 function and therapeutic targeting. Nat Commun. 2017;8:e764. DOI: 10.1038/s41467-017-00836-6

[23] Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ, et al. Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep. 2017;7:e5532. DOI: 10.1038/s41598-017-06002-8

[24] Owen CJ, Stewart DA. Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: Overview and perspective. Ther Adv Hematol. 2015;6(4):161–70. DOI: 10.1177/2040620715586528

[25] Geh D, Gordon C. Epratuzumab for the treatment of systemic lupus erythematosus. Expert Rev Clin Immunol. 2018;14(4):245–58. DOI: 10.1080/1744666X.2018.1450141

[26] Blair HA. Atezolizumab: A review in previously treated advanced non-small cell lung cancer. Target Oncol. 2018;13(3):399–7. DOI: 10.1007/s11523-018-0570-5

[27] Wurz GT, Kao CJ, DeGregorio MW. Novel cancer antigens for personalized immunotherapies: Latest evidence and clinical potential. Ther Adv Med Oncol. 2016;8(1):4–31. DOI: 10.1177/1758834015615514

[28] Huang Y, Furuno M, Arakawa T, Takizawa S, de Hoon M, Suzuki H, et al. A framework for identification of on- and off-target transcriptional responses to drug treatment. Sci Rep. 2019;9(1):e17603. DOI: 10.1038/s41598-019-54180-4

[29] Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95. DOI: 10.1056/NEJMoa022050

[30] Delhanty PJD, Bouw E, Huisman M, Vervenne RML, Themmen APN, van der Lely AJ, et al. Functional characterization of a new human melanocortin-4 receptor homozygous mutation (N72K) that is associated with early-onset obesity. Mol Biol Rep. 2014;41(12):7967–72. DOI: 10.1007/s11033-014-3691-7

[31] Yoshida T, Yoshimura M, Amakura Y. Chemical and biological significance of oenothein B and related ellagitannin oligomers with macrocyclic structure. Molecules. 2018;23(3):e552. DOI: 10.3390/molecules23030552

[32] Gant TG, Shahbaz MM, investors; Auspex Pharmaceuticals, Inc., assignee. Pyrazole carboxamide inhibitors of factor Xa. United States patent 2010O130543A1. 2010 May 27.

[33] Johnson MR, investor; Parion Sciences, Inc., assignee. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity. United States patent 2014.0171447A1. 2014 Jun 19.

[34] Mayer JP, Hsiung HM, Flora DB, Edwards P, Smith DP, Zhang XY, et al. Discovery of a β-MSH-derived MC-4R selective agonist. J Med Chem. 2005;48(9):3095–98. DOI: 10.1021/jm0501432

[35] López C, Burkhardt B, Chan JK, Leoncini L, Mbulaiteye SM, Ogwang MD, et al. Burkitt lymphoma. Nat Rev Dis Primers. 2022;8(1):78. DOI: 10.1038/s41572-022-00404-3

[36] Prica A, Crump M. Improving CD20 antibody therapy: Obinutuzumab in lymphoproliferative disorders. Leuk Lymphoma. 2019;60(3):573–82. DOI: 10.1080/10428194.2018.1498490

[37] Fekih A, Dammak N, Agrebi I, Toumi S, Yaich S, Chaker H, et al. POS-454 mantle cell lymphoma and renal impairment: About 2 cases. Kidney Int Rep. 2021;6(4), Suppl 197.  DOI: 10.1016/j.ekir.2021.03.480

[38] Li M, Liu D, Lee D, Kapoor S, Gibson-Corley KN, Quinn, TP, et al. Enhancing the efficacy of melanocortin 1 receptor-targeted radiotherapy by pharmacologically upregulating the receptor in metastatic melanoma. Mol Pharm. 2019;16(9):3904–15. DOI: 10.1021/acs.molpharmaceut.9b00512

[39] Yoshikawa S, Chen LG, Yoshimura M, Amakura Y, Hatano T, Taniguchi S. Barricyclin D1-a dimeric ellagitannin with a macrocyclic structure-and accompanying tannins from Barringtonia racemosa. Biosci Biotechnol Biochem. 2021;85(7):1609–20. DOI: 10.1093/bbb/zbab073

[40] Hao X, Zuo X, Kang D, Zhang J, Song Y, Liu X, Zhan P. Contemporary medicinal-chemistry strategies for discovery of blood coagulation factor Xa inhibitors. Expert Opin Drug Discov. 2019;14(9):915–31. DOI: 10.1080/17460441.2019.1626821

[41] Schmitz T, Bäuml CA, Imhof D. Inhibitors of blood coagulation factor XIII. Anal Biochem. 2020;605:e113708. DOI: 10.1016/j.ab.2020.113708

[42] Zhuang B, Xu R. Principle and progress of treating lymphoma with CD22 as immunotherapy target. Highl Sci Eng Technol. 36:577–84. DOI: 10.54097/hset.v36i.5733

[43] Willard P, McKay J, Yazbeck V. Role of antibody-based therapy in indolent non-Hodgkin’s lymphoma. Leuk Res Rep. 2021;16:e100275. DOI: 10.1016/j.lrr.2021.100275