In Silico Screening and Designing Synthesis of Cinchona Alkaloids Derivatives as Potential Anticancer


  • Muhammad Hanafi Department of Medical Chemistry, Faculty of Medicine, University of Indonesia
  • Rosmalena Rosmalena Atma Jaya Catholic University of Indonesia
  • Vivitri Dewi Prasasty Research Center for Chemistry, Indonesian Institute of Sciences, Puspiptek Serpong 15314, Indonesia
  • Linar Zalinar Udin Research Center for Chemistry, Indonesian Institute of Sciences, Puspiptek Serpong 15314, Indonesia
  • Gian Primahana Research Center for Chemistry, Indonesian Institute of Sciences, Puspiptek Serpong 15314, Indonesia



Cinchona alkaloids, in silico, anticancer, molecular docking, synthesis


P-glycoprotein (P-gp) resistance in cancer cells decreases intracellular accumulation of various anticancer drugs. This multidrug resistance (MDR) protein can be modulated by a number of non-cytotoxic drugs. We have screened 30 chincona alkaloids derivatives as a potent P-gp inhibitor agent in silico. Hereby, we report the highest potential inhibitions of P-gp is Cinchonidine isobutanoate through molecular docking approach. with affinity energy -8.6 kcal/mol and inhibition constant, Ki is 4.89 x 10-7 M. Cinchonidine isobutanoate is also known has molecular weight below 500, Log P value 3.5, which is indicated violation free of Lipinski`s rule of five. Thus, Cinchonidine isobutanoate is the most potent compound as anticancer compare to other Cinchona alkaloids. Ultimately, we design Cinchonidine isobutanoate for further lead synthesis by using DBSA, act as a combined Brønsted acid-surfactant-catalyst (BASC) to obtain high concentration of organic product by forming micellar aggregates which is very powerful catalytic application in water environment.

Author Biography

Rosmalena Rosmalena, Atma Jaya Catholic University of Indonesia

Faculty of Biotechnology


Callaghan R, Luk F, Bebawy M (2014) Inhibition of the multidrug resistance P-glycoprotein: Time for a change of strategy?. Drug Metabolism and Disposition 42 (4): 623-631. doi: 10.1124/dmd.113.056176.

Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM (2015) P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review. Journal of Advanced Research 6 (1): 45-62. doi: 10.1016/j.jare.2014.11.008.

Davidson AL, Dassa E, Orelle C, Chen J (2008) Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiology Molecular and Biology Reviews 72 (2): 317-364. doi: 10.1128/MMBR.00031-07.

Vasiliou V, Vasiliou K, Nebert DW (2009) Human ATP-binding cassette (ABC) transporter family. Human Genomics 3 (3): 281-290. doi: 10.1186/1479-7364-3-3-281.

Solary E, Mannone L, Moreau D et al. (2000) Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes. Leukemia 14 (12): 2085-2094.

Scagliotti GV, Novello S, Selvaggi G (1999) Multidrug resistance in non-small-cell lung cancer. Annals of Oncology 10 (Suppl 5): S83-86.

Merk J, Rolff J, Dorn C et al. (2011) Chemoresistance in non-small-cell lung cancer: can multidrug resistance markers predict the response of xenograft lung cancer models to chemotherapy? European Journal of Cardio-thorac Surgery 40 (1): e29-33. doi: 10.1016/j.ejcts.2011.02.010.

Peters GJ, Honeywell RJ (2015) Drug transport and metabolism of novel anticancer drugs. Expert Opinion on Drug Metabolism and Toxicology 11 (5): 661-663. doi: 10.1517/17425255.2015.1041255

Wang Y, Qi X, Li D et al. (2014) Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of aspergiolide A in early drug development. Drug Design, Development and Therapy 8: 1965-1977. doi: 10.2147/DDDT.S64989.

Kwon CH (1999) Metabolism-based anticancer drug design. Archives of Pharmacal Research 22 (6): 533-541. doi: 10.1007/BF02975322.

Slordal L, Aarbakke J (1987) Effect of anticancer drugs on

drug metabolism. Pharmacology and Therapeutics 35 (1-2): 217-226. doi: 10.1016/0163-7258(87)90107-0.

Szewczyk P, Tao H, McGrath AP et al. (2015) Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein. Acta Crystallographica D 71 (Pt 3): 732-741. doi: 10.1107/S1399004715000978.

Jin MS, Oldham ML, Zhang Q, Chen J (2012) Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 490 (7421):566-559. doi:10.1038/nature11448.

Li J, Jaimes KF, Aller SG (2014) Refined structures of mouse P-glycoprotein. Protein Science 23 (1): 34-46. doi: 10.1002/pro.2387.

Biasini M, Bienert S, Waterhouse A et al. (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Research 42 (Web Server issue): W252-258. doi: 10.1093/nar/gku340.

Bordoli L, Kiefer F, Arnold K et al. (2009) Protein structure homology modeling using SWISS-MODEL workspace. Nature Protocols 4 (1): 1-13. doi: 10.1038/nprot.2008.197.

Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22 (2): 195-201. doi: 10.1093/bioinformatics/bti770

Schwede T, Kopp J, Guex N, Peitsch MC (2003) SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Research 31 (13): 3381-3385.

Laskowski RA, Rullmannn JA, MacArthur MW et al. (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. Journal of Biomolecular NMR 8 (4): 477-486. doi: 10.1007/BF00228148.

Carugo O, Djinovic-Carugo K (2013) A proteomic Ramachandran plot (PRplot). Amino Acids 44 (2): 781-790. doi: 10.1007/s00726-012-1402-z.

Gopalakrishnan K, Sowmiya G, Sheik SS, Sekar K. Ramachandran plot on the web (2.0). Protein and Peptide Letters 14 (7): 669-671. doi: 10.2174/092986607781483912.

Ho BK, Thomas A, Brasseur R (2003) Revisiting the Ramachandran plot: hard-sphere repulsion, electrostatics, and H-bonding in the alpha-helix. Protein Science 12 (11): 2508-2522. doi: 10.1110/ps.03235203.

Kolaskar AS, Sawant S (1996) Prediction of conformational states of amino acids using a Ramachandran plot. Chemical Biology and Drug Design 47 (1-2): 110-116. doi: 10.1111/j.1399-3011.1996.tb00817.x.

Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Science 2 (9): 1511-1519. doi: 10.1002/pro.5560020916.

Cousins KR (2011) Computer review of ChemDraw Ultra 12.0. Journal of the American Chemical Society 133 (21): 8388. doi: 10.1021/ja204075s.

Li Z, Wan H, Shi Y, Ouyang P (2004) Personal experience with four kinds of chemical structure drawing software: review on ChemDraw, ChemWindow, ISIS/Draw, and ChemSketch. Journal of Chemical Information and Modeling 44 (5): 1886-1890. doi: 10.1021/ci049794h.

Southan C, Stracz A (2013) Extracting and connecting chemical structures from text sources using Journal of Cheminformatics 5 (1): 20. doi: 10.1186/1758-2946-5-20.

Fernandez-Recio J, Totrov M, Abagyan R (2002) Screened charge electrostatic model in protein-protein docking simulations. Pacific Symposium on Biocomputing 2002: 552-563.

Sharom FJ (2011) The P-glycoprotein multidrug transporter. Essays Biochem 50 (1): 161-178. doi: 10.1042/bse0500161.

Kadioglu O, Saeed ME, Valoti M et al. (2016) Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses. Biochemical Pharmacology 104: 42-51. doi: 10.1016/j.bcp.2016.01.014.

Follit CA, Brewer FK, Wise JG, Vogel PD (2015) In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture. Pharmacology Research and Perspectives 3 (5): e00170. doi: 10.1002/prp2.170.

Aller SG, Yu J, Ward A et al. (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323 (5922): 1718-1722. doi: 10.1126/science.1168750.

Badhan R, Penny J (2006) In silico modelling of the interaction of flavonoids with human P-glycoprotein nucleotide-binding domain. European Journal of Medicinal Chemistry 41 (3): 285-295. doi: 10.1016/j.ejmech.2005.11.012.

Akiyama T, Mori K (2015) Stronger bronsted acids: Recent progress. Chemical Reviews 115 (17): 9277-9306. doi: 10.1021/acs.chemrev.5b00041.

Shirakawa S, Kobayashi S (2007) Surfactant-type Bronsted acid catalyzed dehydrative nucleophilic substitutions of alcohols in water. Organic Letters 9 (2): 311-314. doi: 10.1021/ol062813j.

Hiroto S, Shinokubo H, Osuka A (2006) Porphyrin synthesis in water provides new expanded porphyrins with direct bipyrrole linkages: isolation and characterization of two heptaphyrins. Journal of the American Chemical Society 128 (20): 6568-6569. doi: 10.1021/ja061621g.

Manabe K, Iimura S, Sun XM, Kobayashi S (2002) Dehydration reactions in water. Bronsted Acid-surfactant-combined catalyst for ester, ether, thioether, and dithioacetal formation in water. Journal of the American Chemical Society 124 (40): 11971-11978. doi: 10.1021/ja026241j

Gogoi P, Hazarika P, Konwar D (2005) Surfactant/I2/water: an efficient system for deprotection of oximes and imines to carbonyls under neutral conditions in water. The Journal of Organic Chemistry 70 (5): 1934-1936. doi: 10.1021/jo0480287.