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Molecular dynamics simulation studies of betulinic acid with human serum albumin

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Abstract

Betulinic acid (BA) is a naturally occurring pentacyclictriterpenoid possessing anti-retroviral, anti-cancer, and anti-inflammatory properties. Here, we studied the interaction of BA with human serum albumin (HSA) by using molecular docking, and molecular dynamic simulation methods. Molecular docking studies revealed that BA can bind in the large hydrophobic cavity of drug binding site I of sub-domain IIA and IIB, mainly by the hydrophobic interactions and also by hydrogen bond interactions. In which several cyclohexyl groups of BA are interacting with Phe(206), Arg(209), Ala(210), Ala(213), Leu(327), Gly(328), Leu(331), Ala(350), and Lys(351), residues of sub-domain IIA and IIB of HSA by hydrophobic interactions. Also, hydrogen bond interactions were observed between the hydroxyl (OH) group of BA with Phe(206) and Glu(354) of HSA, with hydrogen bond distances of 0.24 nm,0.28 nm respectively. Further, specifically, the molecular dynamics study makes an important contribution in understanding the effect of the binding of BA on conformational changes of HSA and the stability of the protein-drug complex system in aqueous solution. The root mean square deviation values of atoms in the free HSA molecule were calculated from 3000 ps to 5000 ps trajectory and the results were obtained as 0.72 ± 0.036 nm and 0.81 ± 0.032 nm for free HSA and HSA-BA, respectively. The radius of gyration (Rg) values of both unliganded HSA and HSA-BA were stabilized at 2.59 ± 0.03 nm, 2.51 ± 0.01 nm, respectively. Thus, this work may play an important role in the design of new BA inspired drugs with desired HSA binding affinity.

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References

  1. Yogeeswari P, Sriram D (2005) Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 12:657–666

    Article  CAS  Google Scholar 

  2. Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CWW, Fong HHS, Kinghorn AD, Brown DM, Wani MC, Wall ME, Hieken TJ, Das Gupta TK, Pezzuto JM (1995) Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1:1046–1051

    Article  CAS  Google Scholar 

  3. Cichewicz RH, Kouzi SA (2004) Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Med Res Rev 24:90–114

    Article  CAS  Google Scholar 

  4. Chowdhury AR, Mittra N, Sharma S, Mukhopadhyay S, Majumder HK (2002) Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Med Sci Monitor 8:254–265

    Google Scholar 

  5. Ganguly A, Das B, Roy A, Sen N, Dasgupta SB, Mukhopadhayay S, Majumder HK (2007) Betulinic acid, a catalytic inhibitor of topoisomerase i, inhibits reactive oxygen species–mediated apoptotic topoisomerase i–dna cleavable complex formation in prostate cancer cells but does not affect the process of cell death. Cancer Res 67:11848–11858

    Article  CAS  Google Scholar 

  6. Rajendran P, Jaggi M, Singh M, Mukherjee R, Burman A (2008) Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity. Invest New Drugs 26:25–34

    Article  CAS  Google Scholar 

  7. Fulda S, Kroemer G (2009) Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov Today 14:885–890

    Article  CAS  Google Scholar 

  8. Lewis DFV, Dickins M, Weaver RJ, Eddershaw PJ, Goldfarb PS, Tarbit MH (1998) Molecular modeling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of enzyme specificity and site-directed mutagenesis experiments in the CYP2C subfamily. Xenobiotica 28:235–268

    Article  CAS  Google Scholar 

  9. Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M, Matallana C, Castillo A, Zoumplis D, Martin DE, Orenstein JM, Allaway GP, Freed EO, Wild CT (2003) PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag. Proc Natl Acad Sci U S A 100:13555–13560

    Article  CAS  Google Scholar 

  10. Zhou J, Xiong Y, Dismuke D, Forshey BM, Lundquist C, Lee KH, Aiken C, Chen CH (2004) Pharmacologic inhibition of HIV-1 replication by a novel mechanism: specific interference with the final step of virion maturation. J Virol 78:922–929

    Article  CAS  Google Scholar 

  11. Curry S, Mandelkow H, Brick P, Franks N (1998) Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nat Struct Mol Biol 5:827–835

    Article  CAS  Google Scholar 

  12. Curry S, Brick P, Franks NP (1999) Fatty acid binding to human serum albumin: new insights from crystallographic studies. Biochem Biophys Acta (BBA) 1441:131–140

    CAS  Google Scholar 

  13. Bhattacharya AA, Grnne T, Curry S (2000) Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin. J Mol Biol 303:721–732

    Article  CAS  Google Scholar 

  14. Petitpas I, Grune T, Bhattacharya AA, Curry S (2001) Crystal structures of human serum albumin complexed with monounsaturated and polyunsaturated fatty acids. J Mol Biol 314:955–960

    Article  CAS  Google Scholar 

  15. Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M, Curry S (2005) Structural basis of the drug-binding specificity of human serum albumin. J Mol Biol 353:38–52

    Article  CAS  Google Scholar 

  16. Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K (1999) Crystal structure of human serum albumin at 2.5 Å resolution. Protein Eng 12:439–446

    Article  CAS  Google Scholar 

  17. He XM, Carter DC (1992) Atomic structure and chemistry of human serum albumin. Nature 358:209–215

    Article  CAS  Google Scholar 

  18. Chuang VTG, Otagiri M (2001) Flunitrazepam, a 7-nitro-1,4-benzodiazepine that is unable to bind to the indole-benzodiazepine site of human serum albumin. Biochim Biophys Acta 1546:337–345

    Article  CAS  Google Scholar 

  19. Beauchemin R, N'Soukpo KCN, Thomas TJ, Thomas T, Carpentier R, Tajmir-Riahi HA (2007) Polyamine analogues bind human serum albumin. Biomacromolecules 8:3177–3183

    Article  CAS  Google Scholar 

  20. Kanakis CD, Tarantilis PA, Tajmir-Riahi HA, Polissiou MG (2007) Crocetin, dimethylcrocetin, and safranal bind human serum albumin: stability and antioxidative properties. J Agric Food Chem 55:970–977

    Article  CAS  Google Scholar 

  21. Charbonneau D, Beauregard M, Tajmir-Riahi HA (2009) Structural analysis of human serum albumin complexes with cationic lipids. J Phys Chem B 113:1777–1784

    Article  CAS  Google Scholar 

  22. Froehlich E, Mandeville JS, Jennings CJ, Sedaghat-Herati R, Tajmir-Riahi HA (2009) Dendrimers bind human serum albumin. J Phys Chem B 113:6986–6993

    Article  CAS  Google Scholar 

  23. Varshney AS, Ahmad P, Rehan E, Rehan M, Subbarao N, Khan RH (2010) Ligand binding strategies of human serum albumin: how can the cargo be utilized? Chirality 22:77–87

    Article  CAS  Google Scholar 

  24. Subramanyam R, Gollapudi A, Bonigala P, Chinnaboina M, Amooru DG (2009) Betulinic acid binding to human serum albumin: a study of protein conformation and binding affinity. J Photochem Photobiol B 94:8–12

    Article  CAS  Google Scholar 

  25. Subramanyam R, Goud M, Sudhamalla B, Reddeem E, Gollapudi A, Nellaepalli S, Yadavalli V, Chinnaboina M, Amooru DG (2009) Novel binding studies of human serum albumin with trans-feruloyl maslinic acid. J Photochem Photobiol B 95:81–88

    Article  CAS  Google Scholar 

  26. Gokara M, Sudhamalla B, Amooru DG, Subramanyam R (2010) Molecular interaction studies of trimethoxy flavone with human serum albumin. PLoS One 5:e8834

    Article  Google Scholar 

  27. Neelam S, Gokara M, Sudhamalla B, Amooru DG, Subramanyam R (2010) Interaction studies of coumaroyltyramine with human serum albumin and its biological importance. J Phys Chem B 114:3005–3012

    Article  CAS  Google Scholar 

  28. Sudhamalla B, Gokara M, Ahalawat N, Amooru DG, Subramanyam R (2010) Molecular dynamics simulation and binding studies of β-sitosterol with human serum albumin and its biological relevance. J Phys Chem B 114:9054–9062

    Article  CAS  Google Scholar 

  29. Bourassa P, Dubeau S, Maharvi GM, Fauq AH, Thomas TJ, Tajmir-Riahi HA (2011) Binding of antitumor tamoxifen and its metabolites 4-hydroxytamoxifen and endoxifen to human serum albumin. Biochimie 93:1089–1101

    Article  CAS  Google Scholar 

  30. Diaz N, Suarez D, Sordo TSL, Merz KM (2000) Molecular dynamics study of the IIA binding site in human serum albumin: influence of the protonation state of lys195 and lys199. J Med Chem 44:250–260

    Article  Google Scholar 

  31. Si F, Amisaki T (2006) Molecular dynamics study of conformational changes in human serum albumin by binding of fatty acids. Proteins 64:730–739

    Article  Google Scholar 

  32. Si F, Amisaki T (2008) Identification of high affinity fatty acid binding sites on human serum albumin by MM-PBSA method. Biophys J 94:95–103

    Article  Google Scholar 

  33. Deeb O, Rosales-Hernández MC, Gómez-Castro C, Garduño-Juárez R, Correa-Basurto J (2010) Exploration of human serum albumin binding sites by docking and molecular dynamics flexible ligand-protein interactions. Biopolymers 93:161–170

    Article  CAS  Google Scholar 

  34. Morris GM, Goodsell DS, Huey R, Olson AJ (1996) Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4. J Comput Chem 10:293–304

    CAS  Google Scholar 

  35. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  36. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Aided Mol Des 19:1639–1662

    CAS  Google Scholar 

  37. Berendsen HJC, Van der Spoel D, Van Drunen R (1995) GROMACS: A message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  38. Lindahl E, Hess B, van der Spoel D (2001) GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Model 7:306–317

    CAS  Google Scholar 

  39. Van Gunsteren W, Billeter SR, Eising AA, Hünenberger P, Krüger P, Mark A, Scott WRP, Tironi I (1996) Biomolecular Simulation: The GROMOS96 manual and user guide

  40. Van Gunsteren WF, Daura X, Mark AE (2002) GROMOS Force Field. Encycloped Comput Chem 2:1211–1216

    Google Scholar 

  41. Schuttelkopf AW, van Aalten DMF (2004) PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr 60:1355–1363

    Google Scholar 

  42. Li D, Ji B, Sun H (2009) Probing the binding of 8-Acetyl-7-hydroxycoumarin to human serum albumin by spectroscopic methods and molecular modeling. Spectrochim Acta A 73:35–40

    Article  Google Scholar 

  43. Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng 8:127–134

    Article  CAS  Google Scholar 

  44. Li J, Zhu X, Yang C, Shi R (2010) Characterization of the binding of angiotensin II receptor blockers to human serum albumin using docking and molecular dynamics simulation. J Mol Model 16:789–798

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Centre for Modelling Simulation and Design, Department of Science and Technology (DST) and DST-Fund for Improvement of Science and Technology for computational facilities at University of Hyderabad, respectively. CM and MG acknowledge University of Hyderabad for Ph.D fellowship.

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Authors and Affiliations

  1. Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, India

    Chandramouli Malleda, Navjeet Ahalawat & Mahesh Gokara

  2. Department of Biotechnology, University of Hyderabad, Hyderabad, 500046, India

    Navjeet Ahalawat

  3. Department of Plant Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India

    Rajagopal Subramanyam

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  1. Chandramouli Malleda
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  2. Navjeet Ahalawat
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  3. Mahesh Gokara
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  4. Rajagopal Subramanyam
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Correspondence to Rajagopal Subramanyam.

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Chandramouli Malleda and Navjeet Ahalawat contributed equally.

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Malleda, C., Ahalawat, N., Gokara, M. et al. Molecular dynamics simulation studies of betulinic acid with human serum albumin. J Mol Model 18, 2589–2597 (2012). https://doi.org/10.1007/s00894-011-1287-x

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  • DOI: https://doi.org/10.1007/s00894-011-1287-x

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