Molecular and Cellular Biochemistry

, Volume 454, Issue 1–2, pp 45–56 | Cite as

Molecular modeling investigation of the potential mechanism for phytochemical-induced skin collagen biosynthesis by inhibition of the protein phosphatase 1 holoenzyme

  • Pathomwat WongrattanakamonEmail author
  • Piyarat Nimmanpipug
  • Busaban Sirithunyalug
  • Chalermpong Saenjum
  • Supat JiranusornkulEmail author


The most prominent feature of UV-induced photoaged skin is decreased type 1 procollagen. Increase of the TGF-β/Smad signaling through inhibition of the TβRI dephosphorylation by the GADD34–PP1c phosphatase complex represents a promising strategy for the increase in type 1 collagen production and prevention of UV-induced skin photoaging. In this study, the molecular docking and dynamics simulations, and pharmacophore modeling method were run to investigate a possible binding site as well as binding modes between apigenin, daidzein, asiaticoside, obovatol, and astragaloside IV and PP1c. Through docking study, the possible binding site for these phytochemicals was predicted as the hydrophobic (PP1–substrate binding) groove. The result indicates that PP1 is the significant target of these compounds. Moreover, the 20,000-ps MD simulations present that the binding locations and modes predicted by the docking have been slightly changed considering that the MD simulations proffer more reliable details upon the protein–ligand recognition. The MM-GBSA binding free energy calculations and pharmacophore modeling rationally identify that the highly hydrophobic surfaces/pockets at close proximity of the catalytic core are the most favorable binding locations of the herbal compounds, and that some experimental facts upon a possible mechanism of increase in collagen biosynthesis can be explained. The present study theoretically offers the reliable binding target of the herbal compounds, and therefore helps to understanding the action mechanism for natural small molecules that enhance collagen production.


Collagen Herbal compounds Molecular docking Molecular dynamics simulation Photoaging PP1 TGF-β 



The authors would like to thank Inte:Ligand Software-Entwicklungs und Consulting GmbH for providing an academic free license for LigandScout 4.2.1.

Compliance with ethical standards

Conflict of interest

Every author declares no conflict of interest.

Research involving in human and animal rights

This article does not contain any study with human or animal subjects performed by any of the authors.


  1. 1.
    Park B, Hwang E, Seo SA, Cho JG, Yang JE, Yi TH (2018) Eucalyptus globulus extract protects against UVB-induced photoaging by enhancing collagen synthesis via regulation of TGF-beta/Smad signals and attenuation of AP-1. Arch Biochem Biophys 637:31–39. CrossRefGoogle Scholar
  2. 2.
    Gao W, Lin P, Hwang E, Wang Y, Yan Z, Ngo HTT, Yi TH (2018) Pterocarpus santalinus L. regulated ultraviolet b irradiation-induced procollagen reduction and matrix metalloproteinases expression through activation of TGF-beta/Smad and inhibition of the MAPK/AP-1 pathway in normal human dermal fibroblasts. Photochem Photobiol 94:139–149. CrossRefGoogle Scholar
  3. 3.
    Quan T, He T, Kang S, Voorhees JJ, Fisher GJ (2004) Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling. Am J Pathol 165:741–751CrossRefGoogle Scholar
  4. 4.
    He T, Quan T, Shao Y, Voorhees JJ, Fisher GJ (2014) Oxidative exposure impairs TGF-beta pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts. Age (Dordr) 36:9623. CrossRefGoogle Scholar
  5. 5.
    Xu P, Liu J, Derynck R (2012) Post-translational regulation of TGF-β receptor and Smad signaling. FEBS Lett 586:1871–1884. CrossRefGoogle Scholar
  6. 6.
    Sun Z, Park SY, Hwang E, Park B, Seo SA, Cho JG, Zhang M, Yi TH (2016) Dietary Foeniculum vulgare Mill extract attenuated UVB irradiation-induced skin photoaging by activating of Nrf2 and inhibiting MAPK pathways. Phytomedicine 23:1273–1284. CrossRefGoogle Scholar
  7. 7.
    Zhang Y, Wang J, Cheng X, Yi B, Zhang X, Li Q (2015) Apigenin induces dermal collagen synthesis via smad2/3 signaling pathway. Eur J Histochem 59:2467. Google Scholar
  8. 8.
    Zhao D, Shi Y, Dang Y, Zhai Y, Ye X (2015) Daidzein stimulates collagen synthesis by activating the TGF-beta/smad signal pathway. Australas J Dermatol 56:e7–e14. CrossRefGoogle Scholar
  9. 9.
    Lee J, Jung E, Kim Y, Park J, Park J, Hong S, Kim J, Hyun C, Kim YS, Park D (2006) Asiaticoside induces human collagen I synthesis through TGFbeta receptor I kinase (TbetaRI kinase)-independent Smad signaling. Planta Med 72:324–328. CrossRefGoogle Scholar
  10. 10.
    Choi MS, Yoo MS, Son DJ, Jung HY, Lee SH, Jung JK, Lee BC, Yun YP, Pyo HB, Hong JT (2007) Increase of collagen synthesis by obovatol through stimulation of the TGF-beta signaling and inhibition of matrix metalloproteinase in UVB-irradiated human fibroblast. J Dermatol Sci 46:127–137. CrossRefGoogle Scholar
  11. 11.
    Chen B, Li R, Yan N, Chen G, Qian W, Jiang HL, Ji C, Bi ZG (2015) Astragaloside IV controls collagen reduction in photoaging skin by improving transforming growth factor-beta/Smad signaling suppression and inhibiting matrix metalloproteinase-1. Mol Med Rep 11:3344–3348. CrossRefGoogle Scholar
  12. 12.
    Bolton EE, Wang Y, Thiessen PA, Bryant SH (2008) Chap. 12 - PubChem: integrated platform of small molecules and biological activities. In: Wheeler RA, Spellmeyer DC (eds) Annual reports in computational chemistry, Elsevier, New York, pp. 217–241Google Scholar
  13. 13.
    Choy MS, Swingle M, D’Arcy B, Abney K, Rusin SF, Kettenbach AN, Page R, Honkanen RE, Peti W (2017) PP1:tautomycetin complex reveals a path toward the development of PP1-specific inhibitors. J Am Chem Soc 139:17703–17706. CrossRefGoogle Scholar
  14. 14.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN and Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefGoogle Scholar
  15. 15.
    Paul BK, Guchhait N (2011) A spectral deciphering of the binding interaction of an intramolecular charge transfer fluorescence probe with a cationic protein: thermodynamic analysis of the binding phenomenon combined with blind docking study. Photochem Photobiol Sci 10:980–991. CrossRefGoogle Scholar
  16. 16.
    Hamamura K, Chen A, Tanjung N, Takigawa S, Sudo A, Yokota H (2015) In vitro and in silico analysis of an inhibitory mechanism of osteoclastogenesis by salubrinal and guanabenz. Cell Signal 27:353–362. CrossRefGoogle Scholar
  17. 17.
    Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang J, Kollman P (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24:1999–2012. CrossRefGoogle Scholar
  18. 18.
    Joung IS, Cheatham TE IIIrd (2008) Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J Phys Chem B 112:9020–9041. CrossRefGoogle Scholar
  19. 19.
    Li P, Merz KM Jr (2014) Taking into account the ion-induced dipole interaction in the nonbonded model of ions. J Chem Theory Comput 10:289–297. CrossRefGoogle Scholar
  20. 20.
    Wongrattanakamon P, Nimmanpipug P, Sirithunyalug B, Chaiyana W, Jiranusornkul S (2018) Investigation of the skin anti-photoaging potential of Swertia chirayita secoiridoids through the AP-1/matrix metalloproteinase pathway by molecular modeling. Int J Pept Res Ther. Google Scholar
  21. 21.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38, 27 – 8CrossRefGoogle Scholar
  22. 22.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. CrossRefGoogle Scholar
  23. 23.
    Roe DR, Cheatham TE IIIrd (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9:3084–3095. CrossRefGoogle Scholar
  24. 24.
    Wolber G, Langer T (2005) LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 45:160–169. CrossRefGoogle Scholar
  25. 25.
    Liao SY, Mo GQ, Chen JC, Zheng KC (2014) Docking and molecular dynamics studies of the binding between Peloruside A and tubulin. J Enzyme Inhib Med Chem 29:702–709. CrossRefGoogle Scholar
  26. 26.
    Lee J, Jung E, Lee J, Huh S, Kim J, Park M, So J, Ham Y, Jung K, Hyun CG, Kim YS, Park D (2007) Panax ginseng induces human Type I collagen synthesis through activation of Smad signaling. J Ethnopharmacol 109:29–34. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory for Molecular Design and Simulation (LMDS), Faculty of Pharmacy, Department of Pharmaceutical SciencesChiang Mai UniversityChiang MaiThailand
  2. 2.Computational Simulation and Modelling Laboratory (CSML), Faculty of Science, Department of ChemistryChiang Mai UniversityChiang MaiThailand
  3. 3.Faculty of Pharmacy, Department of Pharmaceutical SciencesChiang Mai UniversityChiang MaiThailand

Personalised recommendations