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Identification of a less toxic vinca alkaloid derivative for use as a chemotherapeutic agent, based on in silico structural insights and metabolic interactions with CYP3A4 and CYP3A5

  • Nikhat Saba
  • Alpana Seal
Original Paper

Abstract

Vinca alkaloids are chemotherapeutic agents used in the treatment of both pediatric and adult cancer patients. Cytochrome P450 3A5 (CYP3A5) is 9- to 14-fold more efficient at clearing vincristine than cytochrome P450 3A4 (CYP3A4) is. However, patients who express an inactive form of the polymorphic CYP3A5 enzyme suffer from severe neurotoxicity during vincristine treatment, resulting in chemotherapy failure. Previous studies have found that the addition of new features to the parent drug can enhance its binding affinity to tubulin manyfold and could therefore yield novel anticancer drugs. However, there is no report of any study of the metabolic activities of CYP3A4 and CYP3A5 with respect to vincristine and vinblastine, so we studied the interactions of these two drugs and 15 vinca derivatives with CYP3A4 and CYP3A5 by performing docking studies using GOLD. Six of the vinca derivatives in complexes with CYP3A4 and CYP3A5 were further investigated in 100-ns molecular dynamic simulations. Interaction energies, hydrogen bonds, and linear interaction energies were calculated and principal component analysis was carried out to visualize the binding interface in each complex. The results indicate that the addition of dimethylurea at the C20′ position in vincristine may increase its binding affinity and lead to enhanced interactions with the less polymorphic CYP3A4 rather than CYP3A5. Thus, dimethylurea vincristine may be a useful drug in cancer chemotherapy treatment as it should be significantly less likely than vincristine to induce severe neurotoxicity in patients.

Graphical Abstract

Proposed modification of Vinca alkaloid derivatives to decrease the neurotoxicity level in cancer patients exhibiting CYP3A4 gene rather than polymorphic CYP3A5 gene.

Keywords

Vincristine and vinblastine derivatives Dimethylurea vincristine Chemotherapeutic agents Neurotoxicity Cytochrome P450 3A4 Cytochrome P450 3A5 

Abbreviations

MD

Molecular dynamics simulation

CYP3A4/5

Cytochrome p450 3A4/5

RMSD

Root mean square deviation

RMSF

Root mean square fluctuation

vdW

Van der Waals

HB

Hydrogen bond

Notes

Acknowledgments

We acknowledge the University Grants Commission for MANF, the DST-Purse program, and the BTIS net program of DBT, the Government of India, New Delhi for financial support. We thank Dr. Suman Kumar Nandy and Shri Rajabrata Bhuyan for reading the manuscript and their helpful suggestions.

Supplementary material

894_2018_3611_MOESM1_ESM.docx (5.9 mb)
ESM 1 (DOCX 6083 kb)

References

  1. 1.
    Sears JE, Boger DL (2015) Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure–function properties. Acc Chem Res 48:653–662Google Scholar
  2. 2.
    Svoboda GH, Neuss N, Gorman M (1959) Alkaloids of Vinca rosea Linn. (Catharanthus Roseus G. Don.) V. Preparation and characterization of alkaloids. J Am Pharm Assoc 48:659–666CrossRefGoogle Scholar
  3. 3.
    Lee JC, Harrison D, Timasheff SN (1975) Interaction of vinblastine with calf brain microtubule protein. J Biol Chem 250:9276–9282Google Scholar
  4. 4.
    Prakash V, Timasheff SN (1983) The interaction of vincristine with calf brain tubulin. J Biol Chem 258:1689–1697Google Scholar
  5. 5.
    Egbelakin A, Ferguson MJ, MacGill EA, Lehmann AS, Topletz AR, Quinney SK, Li L, McCammack KC, Hall SD, Renbarger JL (2011) Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 56:361–367CrossRefGoogle Scholar
  6. 6.
    Ishikawa H, Colby DA, Seto S, Va P, Tam A, Kakei H, Rayl TJ, Hwang I, Boger DL (2009) Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues. J Am Chem Soc 131:4904–4916CrossRefGoogle Scholar
  7. 7.
    Fahy J (2001) Modifications in the “upper” velbenamine part of the vinca alkaloids have major implications for tubulin interacting activities. Curr Pharm Des 7:1181–1197Google Scholar
  8. 8.
    Potier P (1980) Synthesis of the antitumor dimeric indole alkaloids from Catharanthus species (vinblastine group). J Nat Prod 43:72–86Google Scholar
  9. 9.
    Kutney JP, Hibino T, Jahngen E, Okutani T, Ratcliffe AH, Treasurywala AM, Wunderly S (1976) Total synthesis of indole and dihydroindole alkaloids. IX. Studies on the synthesis of bisindole alkaloids in the vinblastine–vincristine series. The biogenetic approach. Helv Chim Acta 59:2858–2882Google Scholar
  10. 10.
    Kuehne ME, Matson PA, Bornmann WG (1991) Enantioselective syntheses of vinblastine, leurosidine, vincovaline and 20′-epi-vincovaline. J Organomet Chem 56:513–528CrossRefGoogle Scholar
  11. 11.
    Yokoshima S, Ueda T, Kobayashi S, Sato A, Kuboyama T, Tokuyama H, Fukuyama T (2002) Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 124:2137–2139CrossRefGoogle Scholar
  12. 12.
    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265CrossRefGoogle Scholar
  13. 13.
    Toopchizadeh V, Barzegar M, Rezamand A, Feiz A (2009) Electrophysiological consequences of vincristine contained chemotherapy in children: a cohort study. J Pediatr Neurol 7:351–356Google Scholar
  14. 14.
    Lavoie Smith EM, Li L, Chiang C, Thomas K, Hutchinson RJ, Wells EM, Ho RH, Skiles J, Chakraborty A, Bridges CM, Renbarger J (2015) Patterns and severity of vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. J Peripher Nerv Syst 20:37–46CrossRefGoogle Scholar
  15. 15.
    Ramchandren S, Leonard M, Mody RJ, Donohue JE, Moyer J, Hutchinson R, Gurney JG (2009) Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia. J Peripher Nerv Syst 14:184–189CrossRefGoogle Scholar
  16. 16.
    Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Neben DW, Gelboin HV, Hardwick JR, Meyer UA (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature (London) 331:442–446CrossRefGoogle Scholar
  17. 17.
    Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141CrossRefGoogle Scholar
  18. 18.
    Wienkers LC, Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4:825–833CrossRefGoogle Scholar
  19. 19.
    Niwa T, Murayama N, Imagawa Y, Yamazaki H (2015) Regioselective hydroxylation of steroid hormones by human cytochromes P450. Drug Metab Rev 47:89–110CrossRefGoogle Scholar
  20. 20.
    Zhang YY, Yang L (2009) Interactions between human cytochrome P450 enzymes and steroids: physiological and pharmacological implications. Expert Opin Drug Metab Toxicol 5:621–629CrossRefGoogle Scholar
  21. 21.
    Fedeli L, Colozza M, Boschetti E, Sabalich I, Aristei C, Guerciolini R, Del Favero A, Rossetti R, Tonato M, Rambotti P, Davis S (1989) Pharmacokinetics of vincristine in cancer patients treated with nifedipine. Cancer 64:1805–1811CrossRefGoogle Scholar
  22. 22.
    Zhou-Pan X, Seree E, Zhou X, Placidi M, Maurel P, Barra Y, Rahmani R (1993) Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res 53:5121–5126Google Scholar
  23. 23.
    Dennison JB, Jones DR, Renbarger JL, Hall SD (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharm Exp Ther 321:553–563CrossRefGoogle Scholar
  24. 24.
    Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV (1989) Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 264:10388–10395Google Scholar
  25. 25.
    Koch I, Weil R, Wolbold R, Brockmöller J, Hustert E, Burk O, Nuessler A, Neuhaus P, Eichelbaum M, Zanger U, Wojnowski L (2002) Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 30:1108–1114CrossRefGoogle Scholar
  26. 26.
    Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5:243–272CrossRefGoogle Scholar
  27. 27.
    Lamba JK, Lin YS, Schuetz EG, Thummel KE (2012) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 64:256–269CrossRefGoogle Scholar
  28. 28.
    Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62:162–172CrossRefGoogle Scholar
  29. 29.
    Pollock B, DeBaun M, Camitta BM, Shuster JJ, Ravindranath Y, Pullen DJ, Land VJ, Mahoney Jr DH, Lauer SJ, Murphy SB (2000) Racial differences in the survival of childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 18:813–823Google Scholar
  30. 30.
    Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391CrossRefGoogle Scholar
  31. 31.
    Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE (2012) Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 92:414–417CrossRefGoogle Scholar
  32. 32.
    Gotoh H, Duncan KK, Robertson WM, Boger DL (2011) 10′-Fluorovinblastine and 10′-fluorovincristine: synthesis of a key series of modified vinca alkaloids. ACS Med Chem Lett 2:948–952Google Scholar
  33. 33.
    Boger DL (2015) 10′-Fluorinated vinca alkaloids provide enhanced biological activity against MDR cancer cells. US Patent 8,940,754Google Scholar
  34. 34.
    Leggans EK, Duncan KK, Barker TJ, Schleicher KD, Boger DL (2012) A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20′ urea derivatives. J Med Chem 56:628–639CrossRefGoogle Scholar
  35. 35.
    Bosilkovska M, Lorenzini KI, Uppugunduri CRS, Desmeules J, Daali Y, Escher M (2016) Severe vincristine-induced neuropathic pain in a CYP3A5 nonexpressor with reduced CYP3A4/5 activity: case study. Clin Ther 38:216–220CrossRefGoogle Scholar
  36. 36.
    Lozano JJ, Pastor M, Cruciani G, Gaedt K, Centeno NB, Gago F, Sanz F (2000) 3D-QSAR methods on the basis of ligand–receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands. J Comput Aided Mol Des 14:341–353Google Scholar
  37. 37.
    Stjernschantz E, Oostenbrink C (2010) Improved ligand–protein binding affinity predictions using multiple binding modes. Biophys J 98:2682–2691Google Scholar
  38. 38.
    Yu J, Paine MJI, Maréchal JD, Kemp CA, Ward CJ, Brown S, Sutcliffe MJ, Roberts GC, Rankin EM, Wolf CR (2006) In silico prediction of drug binding to CYP2D6: identification of a new metabolite of metoclopramide. Drug Metab Dispos 34:1386–1392CrossRefGoogle Scholar
  39. 39.
    Molinspiration Cheminformatics. Homepage. http://www.molinspiration.com. Accessed 3 July 2012
  40. 40.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2012) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 64:4–17CrossRefGoogle Scholar
  41. 41.
    Sevrioukova IF, Poulos TL (2010) Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc Natl Acad Sci USA 107:18422–18427Google Scholar
  42. 42.
    Saba N, Bhuyan R, Nandy SK, Seal A (2015) Differential interactions of cytochrome P450 3A5 and 3A4 with chemotherapeutic agent-vincristine: a comparative molecular dynamics study. Anti Cancer Agents Med Chem 15:475–483CrossRefGoogle Scholar
  43. 43.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748CrossRefGoogle Scholar
  44. 44.
    Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein–ligand docking using GOLD. Proteins 52:609–623Google Scholar
  45. 45.
    Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  46. 46.
    Almlof M, Brandsdal BO, Aqvist J (2004) Binding affinity prediction with different force fields: examination of the linear interaction energy method. J Comput Chem 25:124–254CrossRefGoogle Scholar
  47. 47.
    Berendsen HJ, Hayward S (2000) Collective protein dynamics in relation to function. Curr Opin Struct Biol 10:165–169CrossRefGoogle Scholar
  48. 48.
    Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786Google Scholar
  49. 49.
    Niwa T, Yasumura M, Murayama N, Yamazaki H (2014) Comparison of catalytic properties of cytochromes P450 3A4 and 3A5 by molecular docking simulation. Drug Metab Dispos 8:43–50CrossRefGoogle Scholar
  50. 50.
    Sevrioukova IF, Poulos TL (2012) Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand. J Biol Chem 287:3510–3517CrossRefGoogle Scholar
  51. 51.
    Ekroos M, Sjögren T (2006) Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc Natl Acad Sci USA 103:13682–13687Google Scholar
  52. 52.
    Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD (2006) Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos 34:1317–1327CrossRefGoogle Scholar
  53. 53.
    Hansson T, Marelius J, Åqvist J (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comput Aided Mol Des 12:27–35CrossRefGoogle Scholar
  54. 54.
    Aqvist J, Medina C, Samuelsson J (1994) New method for predicting binding affinity in computer-aided drug design. Protein Eng 7:385–391CrossRefGoogle Scholar
  55. 55.
    Kirchmair J, Williamson MJ, Tyzack JD, Tan L, Bond PJ, Bender A, Glen RC (2012) Computational prediction of metabolism: sites, products, SAR, P450 enzyme dynamics, and mechanisms. J Chem Inf Model 52:617–648CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and BiophysicsUniversity of KalyaniKalyaniIndia

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