A Combined 3D-QSAR, Pharmacophore Modelling, and Molecular Docking Study for Plastoquinone Analogues

Abstract

In this study, a set consisting of 39 compounds that are in the literature and carrying Plastoquinone analogues was investigated. The 3D-QSAR study was performed using a field-based method and Partial Least Square (PLS) regression analysis. The generated 3D-QSAR model has sufficient statistical significance and acceptable prediction power with the regression correlation coefficient (r2) at 0.97 and q2 = 0.4. The pharmacophore modelling was carried out and a four-point model (AHHR_3) was generated. Molecular docking was performed with the selected 1IEP protein and the RMSD value for the position of the ligands docked at the two identified active sites was obtained as 0.3669 Å and 0.5535 Å. Docking analysis revealed that the ABQ16 is the best docked ligand with a DockScore of -9.55, followed by AQ2, AQ6 and ABQ11 with scores of -8.56, -8.2 and -7.64, respectively. It was seen that hydrophobic interactions are dominate and the TYR253 residue is responsible for the pi-pi interaction with the aromatic ring.

Keywords

• Plastoquinone Analogues
• 3D-QSAR
• Pharmacophore Modelling
• Molecular Docking
• Charge Density

References

1. Acuña, J., Piermattey, J., Caro, D., Bannwitz, S., Barrios, L., López, J., Ocampo, Y., Vivas-Reyes, R., Aristizábal, F., Gaitán, R., Müller, K., & Franco, L. (2018). Synthesis, Anti-Proliferative Activity Evaluation and 3D-QSAR Study of Naphthoquinone Derivatives as Potential Anti-Colorectal Cancer Agents. Molecules 2018, Vol. 23, Page 186, 23(1), 186. https://doi.org/10.3390/MOLECULES23010186
2. Atkins, P. W. (2001). Physical Chemistry. The Extent of Adsorption. Oxford University Press.
3. Banerjee, S., Azmi, A. S., Padhye, S., Singh, M. W., Baruah, J. B., Philip, P. A., Sarkar, F. H., & Mohammad, R. M. (2010). Structure-activity studies on therapeutic potential of thymoquinone analogs in pancreatic cancer. Pharmaceutical Research, 27(6), 1146–1158. https://doi.org/10.1007/S11095-010-0145-3/FIGURES/8
4. Bassyouni, F. (2017). Molecular Modeling and Biological Activities of New Potent Antimicrobial, Anti-Inflammatory and Anti-Nociceptive of 5-Nitro Indoline-2-One Derivatives. https://doi.org/10.4172/2169-0138.1000148
5. Bayrak, N., Yıldırım, H., Yıldız, M., Radwan, M. O., Otsuka, M., Fujita, M., Ciftci, H. I., & Tuyun, A. F. (2020). A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity. Chemical Biology & Drug Design, 95(3), 343–354. https://doi.org/10.1111/CBDD.13651
6. Bayrak, N., Yıldırım, H., Yıldız, M., Radwan, M. O., Otsuka, M., Fujita, M., Tuyun, A. F., & Ciftci, H. I. (2019). Design, synthesis, and biological activity of Plastoquinone analogs as a new class of anticancer agents. Bioorganic Chemistry, 92, 103255. https://doi.org/10.1016/J.BIOORG.2019.103255
7. Becke, A. D. (1988). Density-functional exchange-energy approximation with correct asymptotic behavior. Physical Review A, 38(6), 3098. https://doi.org/10.1103/PhysRevA.38.3098
8. Belorgey, D., Antoine Lanfranchi, D., & Davioud-Charvet, E. (2013). 1,4-Naphthoquinones and Other NADPH-Dependent Glutathione Reductase- Catalyzed Redox Cyclers as Antimalarial Agents. Current Pharmaceutical Design, 19(14), 2512–2528.

9. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., & Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28(1), 235–242. https://doi.org/10.1093/NAR/28.1.235
10. Bernstein, F. C., Koetzle, T. F., Williams, G. J. B., Meyer, E. F., Brice, M. D., Rodgers, J. R., Kennard, O., Shimanouchi, T., & Tasumi, M. (1977). The protein data bank: A computer-based archival file for macromolecular structures. Journal of Molecular Biology, 112(3), 535–542. https://doi.org/10.1016/S0022-2836(77)80200-3
11. Brandy, Y., Ononiwu, I., Adedeji, D., Williams, V., Mouamba, C., Kanaan, Y., Copeland, R. L., Wright, D. A., Butcher, R. J., Denmeade, S. R., & Bakare, O. (2012). Synthesis and cytotoxic activities of some 2-Arylnaphtho [2,3-d]oxazole-4,9-dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines. Investigational New Drugs, 30(4), 1709–1714. https://doi.org/10.1007/S10637-011-9635-3/TABLES/2
12. Brannon-Peppas, L., & Blanchette, J. O. (2004). Nanoparticle and targeted systems for cancer therapy. Advanced Drug Delivery Reviews, 56(11), 1649–1659. https://doi.org/10.1016/J.ADDR.2004.02.014
13. Ciftci, H. I., Bayrak, N., Yıldırım, H., Yıldız, M., Radwan, M. O., Otsuka, M., Fujita, M., & Tuyun, A. F. (2019). Discovery and structure–activity relationship of plastoquinone analogs as anticancer agents against chronic myelogenous leukemia cells. Archiv Der Pharmazie, 352(12), 1900170. https://doi.org/10.1002/ARDP.201900170
14. Consonni, V., & Todeschini, R. (2009). Molecular Descriptors for Chemoinformatics: Volume I: Alphabetical Listing/Volume II: Appendices, References. John Wiley & Sons, Ltd.
15. Dey, D., Ray, R., & Hazra, B. (2014). Antitubercular and Antibacterial Activity of Quinonoid Natural Products Against Multi-Drug Resistant Clinical Isolates. Phytotherapy Research, 28(7), 1014–1021. https://doi.org/10.1002/PTR.5090
16. Du, X., Li, Y., Xia, Y. L., Ai, S. M., Liang, J., Sang, P., Ji, X. L., & Liu, S. Q. (2016). Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods. International Journal of Molecular Sciences 2016, Vol. 17, Page 144, 17(2), 144. https://doi.org/10.3390/IJMS17020144
17. Evans, D. A., Doman, T. N., Thorner, D. A., & Bodkin, M. J. (2007). 3D QSAR methods: Phase and catalyst compared. Journal of Chemical Information and Modeling, 47(3), 1248–1257. https://doi.org/10.1021/CI7000082/ASSET/IMAGES/MEDIUM/CI7000082N00001.GIF
18. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Petersson, G. A., Nakatsuji, H., Li, X., Caricato, M., Marenich, A., Bloino, J., Janesko, B. G., Gomperts, R., Mennucci, B., Hratchian, H. P., Ortiz, J. V., … Fox, D. J. (2016). Gaussian 09 (Revision A.02). Gaussian, Inc.
19. Glamočlija, U., Padhye, S., Špirtović-Halilović, S., Osmanović, A., Veljović, E., Roca, S., Novaković, I., Mandić, B., Turel, I., Kljun, J., Trifunović, S., Kahrović, E., Pavelić, S. K., Harej, A., Klobučar, M., & Završnik, D. (2018). Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone. Molecules 2018, Vol. 23, Page 3297, 23(12), 3297. https://doi.org/10.3390/MOLECULES23123297
20. Godoy-Castillo, C., Bravo-Acuña, N., Arriagada, G., Faunes, F., León, R., & Soto-Delgado, J. (2021). Identification of the naphthoquinone derivative inhibitors binding site in heat shock protein 90: an induced-fit docking, molecular dynamics and 3D-QSAR study. Journal of Biomolecular Structure and Dynamics, 39(16), 5977–5987. https://doi.org/10.1080/07391102.2020.1803134/SUPPL_FILE/TBSD_A_1803134_SM9783.PDF
21. Gottesman, M. M. (2001). MECHANISMS OF CANCER DRUG RESISTANCE.
22. Greenwood, J. R., Calkins, D., Sullivan, A. P., & Shelley, J. C. (2010). Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. Journal of Computer-Aided Molecular Design, 24(6–7), 591–604. https://doi.org/10.1007/S10822-010-9349-1/FIGURES/6
23. Halgren, T. (2007). New Method for Fast and Accurate Binding-site Identification and Analysis. Chemical Biology & Drug Design, 69(2), 146–148. https://doi.org/10.1111/J.1747-0285.2007.00483.X
24. Halgren, T. A. (2009). Identifying and characterizing binding sites and assessing druggability. Journal of Chemical Information and Modeling, 49(2), 377–389. https://doi.org/10.1021/CI800324M/ASSET/IMAGES/MEDIUM/CI-2008-00324M_0006.GIF
25. Harder, E., Damm, W., Maple, J., Wu, C., Reboul, M., Xiang, J. Y., Wang, L., Lupyan, D., Dahlgren, M. K., Knight, J. L., Kaus, J. W., Cerutti, D. S., Krilov, G., Jorgensen, W. L., Abel, R., & Friesner, R. A. (2016). OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. Journal of Chemical Theory and Computation, 12(1), 281–296. https://doi.org/10.1021/ACS.JCTC.5B00864/SUPPL_FILE/CT5B00864_SI_001.ZIP
26. Hirshfeld, F. L. (1977). Bonded-atom fragments for describing molecular charge densities. Theoretica Chimica Acta 1977 44:2, 44(2), 129–138. https://doi.org/10.1007/BF00549096
27. Janeczko, M., Demchuk, O. M., Strzelecka, D., Kubiński, K., & Masłyk, M. (2016). New family of antimicrobial agents derived from 1,4-naphthoquinone. European Journal of Medicinal Chemistry, 124, 1019–1025. https://doi.org/10.1016/J.EJMECH.2016.10.034
28. Johnson-Ajinwo, O. R., Ullah, I., Mbye, H., Richardson, A., Horrocks, P., & Li, W. W. (2018). The synthesis and evaluation of thymoquinone analogues as anti-ovarian cancer and antimalarial agents. Bioorganic & Medicinal Chemistry Letters, 28(7), 1219–1222. https://doi.org/10.1016/J.BMCL.2018.02.051
29. Jordão, A. K., Novais, J., Leal, B., Escobar, A. C., Dos Santos Júnior, H. M., Castro, H. C., & Ferreira, V. F. (2013). Synthesis using microwave irradiation and antibacterial evaluation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-naphthoquinones. European Journal of Medicinal Chemistry, 63, 196–201. https://doi.org/10.1016/J.EJMECH.2013.01.010
30. Kadela-Tomanek, M., Jastrzębska, M., Pawełczak, B., Bębenek, E., Chrobak, E., Latocha, M., Książek, M., Kusz, J., & Boryczka, S. (2017). Alkynyloxy derivatives of 5,8-quinolinedione: Synthesis, in vitro cytotoxicity studies and computational molecular modeling with NAD(P)H:Quinone oxidoreductase 1. European Journal of Medicinal Chemistry, 126, 969–982. https://doi.org/10.1016/J.EJMECH.2016.12.031
31. Kunnumakkara, A. B., Bordoloi, D., Sailo, B. L., Roy, N. K., Thakur, K. K., Banik, K., Shakibaei, M., Gupta, S. C., & Aggarwal, B. B. (2019). Cancer drug development: The missing links. Experimental Biology and Medicine, 244(8), 663–689. https://doi.org/10.1177/1535370219839163/ASSET/IMAGES/LARGE/10.1177_1535370219839163-FIG2.JPEG
32. Lee, C., Yang, W., & Parr, R. G. (1988). Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B, 37(2), 785. https://doi.org/10.1103/PhysRevB.37.785
33. López-Lira, C., Alzate-Morales, J. H., Paulino, M., Mella-Raipán, J., Salas, C. O., Tapia, R. A., & Soto-Delgado, J. (2018). Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives. Chemical Biology & Drug Design, 91(1), 29–38. https://doi.org/10.1111/CBDD.13051
34. Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design, 27(3), 221–234. https://doi.org/10.1007/S10822-013-9644-8/TABLES/9
35. McKinnon, J. J., Mitchell, A. S., & Spackman, M. A. (1998). Hirshfeld surfaces: a new tool for visualising and exploring molecular crystals. Chemistry–A European Journal, 4(11), 2136–2141.
36. Miller, M. D., Sheridan, R. P., & Kearsley, S. K. (1999). SQ: A program for rapidly producing pharmacophorically relevent molecular superpositions. Journal of Medicinal Chemistry, 42(9), 1505–1514. https://doi.org/10.1021/JM9806143/SUPPL_FILE/JM9806143_S.PDF
37. Nagar, B., Bornmann, W. G., Pellicena, P., Schindler, T., Veach, D. R., Miller, W. T., Clarkson, B., & Kuriyan, J. (2002). Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571). Biochemistry and Biophysics, 62(15), 4236–4243.
38. Olgen, S. (2018). Overview on Anticancer Drug Design and Development. Current Medicinal Chemistry, 25(15), 1704–1719. https://doi.org/10.2174/0929867325666171129215610
39. Ravichandiran, P., Premnath, D., & Vasanthkumar, S. (2014). Synthesis, molecular docking and antibacterial evaluation of new 1,4-naphthoquinone derivatives contains carbazole-6,11-dione moiety. Journal of Chemical Biology 2014 7:3, 7(3), 93–101. https://doi.org/10.1007/S12154-014-0115-Z
40. Ryu, C. K., Oh, S. Y., Choi, S. J., & Kang, D. Y. (2014). Synthesis of Antifungal Evaluation of 2H-[1,2,3]Triazolo[4,5-g]isoquinoline-4,9-diones. Chemical and Pharmaceutical Bulletin, 62(11), c14-00527. https://doi.org/10.1248/CPB.C14-00527
41. Schrödinger Releae: Phase (No. 4). (2020). Schrödinger, LLC.
42. Schrödinger Release: Epik (No. 4). (2020). Schrödinger, LLC.
43. Schrödinger Release: Glide, (No. 4). (2020). Schrödinger, LLC.
44. Schrödinger Release: LigPrep (No. 4). (2020). Schrödinger, LLC.
45. Schrödinger Release: SiteMap (No. 4). (2020). Schrödinger, LLC.
46. Schrödinger Release (No. 4). (2020). Maestro, Schrödinger, LLC.
47. Sendl, A., Chen, J. L., Jolad, S. D., Stoddart, C., Rozhon, E., Kernan, M., Nanakorn, W., & Balick, M. (1996). Two New Naphthoquinones with Antiviral Activity from Rhinacanthus nasutus. Journal of Natural Products, 59(8), 808–811. https://doi.org/10.1021/NP9601871
48. Seth, S. K., Maity, G. C., & Kar, T. (2011). Structural elucidation, Hirshfeld surface analysis and quantum mechanical study of para-nitro benzylidene methyl arjunolate. Journal of Molecular Structure, 1000(1–3), 120–126. https://doi.org/10.1016/J.MOLSTRUC.2011.06.003
49. Shelley, J. C., Cholleti, A., Frye, L. L., Greenwood, J. R., Timlin, M. R., & Uchimaya, M. (2007). Epik: A software program for pKa prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design, 21(12), 681–691. https://doi.org/10.1007/S10822-007-9133-Z/TABLES/5
50. Shi, J., Long, T., Zhou, Y., Wang, L., Jiang, C., Pan, D., & Zhu, X. (2021). Efficiency and Quantitative Structure-Activity Relationship of Monoaromatics Oxidation by Quinone-Activated Persulfate. Frontiers in Chemistry, 9, 172. https://doi.org/10.3389/FCHEM.2021.580643/XML/NLM
51. Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, 66(1), 7–30. https://doi.org/10.3322/CAAC.21332
52. Sousa, S. F., Ribeiro, A. J. M., Coimbra, J. T. S., Neves, R. P. P., Martins, S. A., Moorthy, N. S. H. N., Fernandes, P. A., & Ramos, M. J. (2013). Protein-Ligand Docking in the New Millennium – A Retrospective of 10 Years in the Field. Current Medicinal Chemistry, 20(18), 2296–2314.
53. Spackman, M. A., & Byrom, P. G. (1997). A novel definition of a molecule in a crystal. Chemical Physics Letters, 267(3–4), 215–220. https://doi.org/10.1016/S0009-2614(97)00100-0
54. Spackman, M. A., & Jayatilaka, D. (2009). Hirshfeld surface analysis. CrystEngComm, 11(1), 19–32. https://doi.org/10.1039/B818330A
55. Spackman, M. A., & McKinnon, J. J. (2002). Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm, 4(66), 378–392.
56. Tropsha, A. (2010). Best Practices for QSAR Model Development, Validation, and Exploitation. Molecular Informatics, 29(6–7), 476–488. https://doi.org/10.1002/MINF.201000061
57. Turner, M., Kinnon, J. M., S. Wolff, Grimwood, D., Spackman, P., Jayatilaka, D., & Spackman, M. (2017). CrystalExplorer17. University of Western Australia.
58. Vidler, L. R., Brown, N., Knapp, S., & Hoelder, S. (2012). Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. Journal of Medicinal Chemistry, 55(17), 7346–7359. https://doi.org/10.1021/JM300346W/SUPPL_FILE/JM300346W_SI_002.PDF
59. Wellington, K. W. (2015). Understanding cancer and the anticancer activities of naphthoquinones-a review. https://doi.org/10.1039/c4ra13547d
60. Wellington, K. W., Kolesnikova, N. I., Nyoka, N. B. P., & McGaw, L. J. (2019). Investigation of the antimicrobial and anticancer activity of aminonaphthoquinones. Drug Development Research, 80(1), 138–146. https://doi.org/10.1002/DDR.21477