In-Silico Assessments of Fruticulin-A and Demethylfruticulin-A Isolated from Salvia Species Against Important Anticancer Targets

Document Type : Original paper

Authors

Department of Molecular Physiology, Agricultural Biotechnology Research Institute of Iran, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.

Abstract

Background and objectives: Bioactive compounds derived from plants have been used to treat various ailments with minimal adverse effects. The in-silico methods are developed to predict the behavior of drug candidates before performing the in-vitro and in-vivo experiments. In the current study, a computational investigation was conducted to understand the probable mechanisms of two benzoquinone diterpenoids namely fruticulin-A and demethylfruticulin-A isolated from several salvia species by molecular docking and dynamic simulation approaches. Methods: The above mentioned compounds with proven anticancer activity were docked against five selected target proteins that regulate cell proliferation and apoptosis including cyclin-dependent protein kinase 2 (CDK-2), CDK-6, DNA topoisomerases I (topo I), topo II and B-cell lymphoma-2 (Bcl-2) using autodock 4.2. Besides, molecular dynamics simulations were applied to evaluate the stability of the best-docked complexes. Results: Both compounds demonstrated remarkable binding affinity to CDK-2 than the known CDK-2 inhibitor. The trajectory analysis for 50 nanosecond (ns) revealed acceptable RMSD, RMSF and Rg values during the entire molecular dynamic simulation which confirmed the stability of complexes. Conclusion: The results of our study displayed that fruticulin-A and demethylfruticulin-A can be developed as excellent natural product derived CDK-2 inhibitors, and further biological experiments should be performed to confirm their use as an efficient option for treating cancer disease.

Keywords

Main Subjects


  • Slamon D, Pegram M. Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol. 2001; 28(3): 13–19.
  • Alam P, Tyagi R, Farah MA, Rehman MT, Hussain A, AlAjmi MF, Siddiqui NA, Al-Anazi KM, Amin S, Mujeeb M. Cytotoxicity and molecular docking analysis of racemolactone I, a new sesquiterpene lactone isolated from Inula racemosa. Pharm Biol. 2021; 59(1): 941–952.
  • Kolšek K, Mavri J, Sollner Dolenc M, Gobec S, Turk S. Endocrine disruptome an open source prediction tool for assessing endocrine disruption potential through nuclear receptor binding. J Chem Inf Model. 2014; 54(4): 1254–1267.
  • Gach K, Długosz A, Janecka A. The role of oxidative stress in anticancer activity of sesquiterpene lactones. Naunyn-Schmiedeb Arch Pharmacol. 2015; 388(5): 477–486.
  • Piccinelli AC, Figueiredo de Santana Aquino D, Morato PN, Kuraoka-Oliveira ÂM, Strapasson RLB, Dos Santos EP, Stefanello MÉA, Oliveira RJ, Kassuya CAL. Anti-inflammatory and antihyperalgesic activities of ethanolic extract and fruticulin a from Salvia lachnostachys leaves in mice. Evid Based Complement Altern Med. 2014; Article ID 835914.
  • Rodríguez-Hahn L, Esquivel B, Sánchez C, Estebanes L, Cárdenas J, Soriano-García M, Toscano R, Ramamoorthy T. Abietane type diterpenoids from Salvia fruticulosa. A revision of the structure of fruticulin B. Phytochemistry. 1989; 28(2): 567–570.
  • Bisio A, Romussi G, Russo E, Cafaggi S, Schito AM, Repetto B, De Tommasi N. Antimicrobial activity of the ornamental species Salvia corrugata, a potential new crop for extractive purposes. J Agric Food Chem. 2008; 56(22): 10468–10472.
  • Valant-Vetschera KM, Roitman JN, Wollenweber E. Chemodiversity of exudate flavonoids in some members of the Lamiaceae. Biochem Syst Ecol. 2003; 31(11): 1279–1289.
  • Oliveira CS, Salvador MJ, de Carvalho JE, Barison A. Cytotoxic abietane-derivative diterpenoids of Salvia lachnostac Phytochem Lett. 2016; 17: 140–143.
  • Corso CR, Stipp MC, Radulski DR, Mariott M, da Silva LM, de Souza Ramos EA, Klassen G, Queiroz Telles JE, Oliveira CS, Stefanello MÉA, Verhoeven AJ, Oude Elferink RPJ, Acco A. Fruticuline A, a chemically-defined diterpene, exerts antineoplastic effects in vitro and in vivo by multiple mechanisms. Sci Rep. 2020; 10(1): 1–14.
  • Monticone M, Bisio A, Daga A, Giannoni P, Giaretti W, Maffei M, Pfeffer U, Romeo F, Quarto R, Romussi G. Demethyl fruticulin A (SCO‐1) causes apoptosis by inducing reactive oxygen species in mitochondria. J Cell Biochem. 2010; 111(5): 1149–1159.
  • Giacomelli E, Bertrand S, Nievergelt A, Zwick V, Simoes-Pires C, Marcourt L, Rivara-Minten E, Cuendet M, Bisio A, Wolfender JL. Cancer chemopreventive diterpenes from Salvia corrugata. 2013; 96: 257–264.
  • Pires DE, Blundell TL, Ascher DB. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015; 58(9): 4066–4072.
  • Mirzaei HH, Firuzi O, Jassbi AR. Diterpenoids from roots of Salvia lachnocalyx; in-silico and in-vitro toxicity against human cancer cell lines. Iran J Pharm Sci. 2020; 19(4): 85–94.
  • Webb B, Sali A. Comparative protein structure modeling using MODELLER. Curr Protoc Bioinformatics. 2016; 54(1): 1–57.
  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16): 2785–2791.
  • Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7: 1–13.
  • Daina A, Zoete V. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. Chem Med Chem. 2016; 11(11): 1117–1121.
  • Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr. 1993; 26(2): 283–291.
  • Kawatsuki A, Yasunaga J, Mitobe Y, Green PL, Matsuoka M. HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4+ T cells. Oncogene. 2016; 35(34): 4509–4517.
  • Gurung AB, Ali MA, Lee J, Farah MA, Al-Anazi KM. Molecular docking and dynamics simulation study of bioactive compounds from Ficus carica with important anticancer drug targets. PLoS One. 2021; Article ID 0254035.