IN SILICO IDENTIFICATION OF APOBEC3B SMALL MOLECULE INHIBITORS FROM DTP-NCI LIBRARIES
Objective: APOBEC3B (A3B) enzyme causes C-to-T or C-to-G somatic alteration in the cancer genome, leading to the evolution of a broad spectrum of human cancers. The present study aims to identify A3B small molecule inhibitors using a top-down approach via pharmacoinformatic virtual screening.
Methods: Virtual screening of 2951 drug-alike molecules with diversified structures from the National Cancer Institute Development Therapeutics Program (DTP-NCI) compounds library was performed using GOLD and AutoDock Vina docking programs against the 3D structure of A3B (PDB ID: 5TD5).
Results: Amongst the docked compounds, Nordracorubin, NSC641233 and Raloxifene hydrochloride showed the most potent binding affinities towards A3B on both Autodock/Vina and GOLD. Several significant similarities were observed between A3B and the three hits, including hydrogen bonds and pi-pi stacking. The three compounds also exhibited interaction with the centralized zinc cofactor and amino acid residues that directly contribute the deaminase activity of A3B enzyme.
Conclusion: We hypothesize that the findings from this study could significantly shorten the quest for novel molecules against the A3B after confirmation with subsequent in vitro and in vivo studies in the near future.
2. Shi K, Carpenter MA, Banerjee S, Shaban NM, Kurahashi K, Salamango DJ, et al. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat Struct Mol Biol 2017;24:131-9
3. Salter JD, Bennett RP, Smith HC. The APOBEC Protein Family: United by Structure, Divergent in Function. Trends Biochem Sci 2016;41:578-94.
4. Alexandrov, L. B., Nik-Zainal, S., Wedge D. Signatures of mutational processes in human cancer. Nature 2013;500:415–21.
5. Burns MB, Temiz NA, Harris RS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 2013;45:977-83.
6. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al. An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers. Nat Genet 2013;45: 970-6.
7. Sieuwerts AM, Willis S, Burns MB, Look MP, Meijer-Van Gelder ME, Schlicker A, et al. Elevated APOBEC3B Correlates with Poor Outcomes for Estrogen-Receptor-Positive Breast Cancers. Horm Cancer 2014;5:405-13.
8. Harris RS. Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer. Breast Cancer Res 2015;17:8.
9. Law EK, Sieuwerts AM, Lapara K, Leonard B, Starrett GJ, Molan AM, et al. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Sci Adv 2016;2: e1601737.
10. Choowongkomon K, Sawatdichaikul O, Songtawee N, Limtrakul J. Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database. Molecules 2010;15:4041-54.
11. Zhou X, Yu S, Su J, Sun L. Computational study on new natural compound inhibitors of pyruvate dehydrogenase kinases. Int J Mol Sci 2016;17:340.
12. Matsumoto T, Shirakawa K, Yokoyama M, et al. Protein kinase A inhibits tumor mutator APOBEC3B through phosphorylation. Sci Rep 2019;9:8307.
13. Trott O, Olson AJ. Autodock vina: improving the speed and accuracy of docking. J Comput Chem 2010;31:455-61.
14. Dallakyan S, Olson AJ. Small-Molecule Library Screening by Docking with PyRx. Methods Mol Biol 2015;1263:243–50.
15. Arokiyaraj S, Stalin A, Shin H. Anti-methanogenic effect of rhubarb (Rheum spp.) – An in silico docking studies on methyl-coenzyme M reductase (MCR). Saudi J Biol Sci 2019;26:1458-62.
16. Jha NK, Kumar P. Molecular docking studies for the comparative analysis of different biomolecules to target hypoxia inducible factor-1?. Int J Appl Pharm 2017;9:83-9.
17. Nazwir N, Yanuar A, Syahdi RR. In Silico investigation of echinodermata secondary metabolites as human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors. Int J Appl Pharm 2020;12:51-5.
18. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and Validation of a Genetic Algorithm for Flexible Docking. J Mol Biol 1997;267:727-48.
19. Byeon IJL, Byeon CH, Wu T, Mitra M, Singer D, Levin JG, et al. Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity. Biochemistry 2016;55:2944-59.
20. Cauët E, Rooman M, Wintjens R, Liévin J, Biot C. Histidine-aromatic interactions in proteins and protein-ligand complexes: Quantum chemical study of X-ray and model structures. J Chem Theory Comput 2005;1:472-83.
21. Singh RK, Tiwari MK, Kim I-W, Chen Z, Lee J-K. Probing the Role of Sigma ? Interaction and Energetics in the Catalytic Efficiency of Endo-1,4-?-Xylanase. Appl Environ Microbiol 2012;78:8817-21.
22. Gupta D, Bleakley B, Gupta RK. 'Dragon's blood: Botany, chemistry and therapeutic uses. J Ethnopharmacol 2007;115:361-80.
23. González AG, León F, Sánchez-Pinto L, Padrón JI, Bermejo J. Phenolic compounds of Dragon’s blood from Dracaena draco. J Nat Prod 2000;63:1297-9.
24. Yi T, Chen HB, Zhao ZZ, Yu ZL, Jiang ZH. Comparison of the chemical profiles and antiplatelet aggregation effects of two ""'dragon's Blood"" drugs used in traditional Chinese medicine. J Ethnopharmacol 2011;133:796-802.
25. Sun J, Liu JN, Fan B, Chen XN, Pang DR, Zheng J, et al. Phenolic constituents, pharmacological activities, quality control, and metabolism of Dracaena species: A review. J Ethnopharmacol 2019;244:112138.
26. Schmid M, Trauner D. Biomimetic Synthesis of Complex Flavonoids Isolated from Daemonorops ""Dragon's Blood." Angew Chemie - Int Ed. 2017;56:12332-5.
27. He Y, Ju W, Hao H, Liu Q, Lv L, Zeng F. Dracorhodin perchlorate suppresses proliferation and induces apoptosis in human prostate cancer cell line PC-3. J Huazhong Univ Sci Technol - Med Sci 2011;31:215-9.
28. Xia MY, Wang MW, Cui Z, Tashiro SI, Onodera S, Minami M, et al. Dracorhodin perchlorate induces apoptosis in HL-60 cells. J Asian Nat Prod Res 2006;8:335-43.
29. Xia M, Wang D, Wang M, Tashiro SI, Onodera S, Minami M, et al. Dracorhodin perchlorate induces apoptosis via activation of caspases and generation of reactive oxygen species. J Pharmacol Sci 2004;95:273-83.
30. Yu J hua, Zheng G bin, Liu C yu, Zhang LY, Gao HM, Zhang YH, et al. Dracorhodin perchlorate induced human breast cancer MCF-7 apoptosis through mitochondrial pathways. Int J Med Sci 2013;10:1149-56.
31. Shoda T, Kato M, Fujisato T, Misawa T, Demizu Y, Inoue H, et al. Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator. Bioorg Med Chem 2016;24:2914-9.
32. Xu L, Lei J, Jiang D, Zhou L, Wang S, Fan W. Reversal effects of Raloxifene on paclitaxel resistance in 2 MDR breast cancer cells. Cancer Biol Ther 2015;16:1794-801.
33. Tu Z, Li H, Ma Y, Tang B, Tian J, Akers W, et al. The enhanced antiproliferative response to combined treatment of trichostatin A with Raloxifene in MCF-7 breast cancer cells and its relevance to estrogen receptor ? expression. Mol Cell Biochem. 2012;366(1-2):111-22.
34. El-Gamal MI, Ullah S, Zaraei SO, Jalil S, Zaib S, Zaher DM, Omar HA, et al. Synthesis, biological evaluation, and docking studies of new raloxifene sulfonate or sulfamate derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase. Eur J Med Chem 2019;181:111560.
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