Scaffold-based Screening and Molecular Dynamics Simulation Study to Identify Two Structurally Related Phenolic Compounds as Potent MMP1 Inhibitors

Swagata      Patra; Parameswaran      Saravanan; Bhaskar      Das; Venkatesan      Subramanian; Sanjukta      Patra

doi:10.2174/1386207323666200428114216

Abstract

Background: Matrix metalloproteinase 1 are zinc-dependent endopeptidases responsible for the controlled breakdown of the extracellular matrix resulting in the maintenance of homeostasis. Dysregulation of MMP1 leads to the progression of various pathological conditions like cancer, rheumatoid arthritis, cardiovascular disease, skin damage and fibrotic disorder. Thus, MMP1 inhibition is the potential drug target of many synthetic MMP1 inhibitors but lack of substrate specificity hinders their clinical applicability. Hence, inhibitors from natural products have gained widespread attention.

Objective: The present study attempts screening of novel MMP1 inhibitors from the ZINC database based on experimentally reported natural inhibitors of MMP1 as a scaffold.

Methods: Molecular docking study was performed with 19 experimentally reported natural inhibitors spanning across nine different classes followed by virtual screening using the selected compounds. The selected compounds were subjected to molecular dynamics simulation.

Results: Twenty compounds were screened with a cut-off of -9.0 kcal/mol of predicted free energy of binding, which further converged to 6 hits after docking studies. After comparing the docking result of 6 screened hits, two best compounds were selected. ZINC02436922 had the best interaction with six hydrogen bond formation to a relatively confined region in the S1’site of MMP1 and -10.01 kcal/mol of predicted free energy of binding. ZINC03075557 was the secondbest compound with -9.57 kcal/mol predicted binding free energy. Molecular dynamics simulation of ZINC02436922 and ZINC03075557 corroborates docking study.

Conclusion: This study indicated phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.

Keywords: MMP1, natural inhibitor, virtual screening, molecular docking, molecular dynamics simulation, phenolics.

« Previous Next »

[1] 
Egeblad, M.; Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer,  2002, 2(3), 161-174.
[http://dx.doi.org/10.1038/nrc745 ] [PMID:  11990853] 
[2] 
Terp, G.E.; Cruciani, G.; Christensen, I.T.; Jørgensen, F.S. Structural differences of matrix metalloproteinases with potential implications for inhibitor selectivity examined by the GRID/CPCA approach. J. Med. Chem.,  2002, 45(13), 2675-2684.
[http://dx.doi.org/10.1021/jm0109053 ] [PMID:  12061871] 
[3] 
Overall, C.M.; López-Otín, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat. Rev. Cancer,  2002, 2(9), 657-672.
[http://dx.doi.org/10.1038/nrc884 ] [PMID:  12209155] 
[4] 
Aureli, L.; Gioia, M.; Cerbara, I.; Monaco, S.; Fasciglione, G.F.; Marini, S.; Ascenzi, P.; Topai, A.; Coletta, M. Structural bases for substrate and inhibitor recognition by matrix metalloproteinases. Curr. Med. Chem.,  2008, 15(22), 2192-2222.
[http://dx.doi.org/10.2174/092986708785747490 ] [PMID:  18781944] 
[5] 
Maskos, K. Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie,  2005, 87(3-4), 249-263.
[http://dx.doi.org/10.1016/j.biochi.2004.11.019 ] [PMID:  15781312] 
[6] 
Pavlaki, M.; Zucker, S. Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev.,  2003, 22(2-3), 177-203.
[http://dx.doi.org/10.1023/A:1023047431869 ] [PMID:  12784996] 
[7] 
Coussens, L.M.; Fingleton, B.; Matrisian, L.M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science,  2002, 295(5564), 2387-2392.
[http://dx.doi.org/10.1126/science.1067100 ] [PMID:  11923519] 
[8] 
Spurlino, J.C.; Smallwood, A.M.; Carlton, D.D.; Banks, T.M.; Vavra, K.J.; Johnson, J.S.; Cook, E.R.; Falvo, J.; Wahl, R.C.; Pulvino, T.A.; Wendoloski, J.J. 1.56 A structure of mature truncated human fibroblast collagenase. Proteins,  1994, 19(2), 98-109.
[http://dx.doi.org/10.1002/prot.340190203 ] [PMID:  8090713] 
[9] 
Hu, X.; Balaz, S.; Shelver, W.H. A practical approach to docking of zinc metalloproteinase inhibitors. J. Mol. Graph. Model.,  2004, 22(4), 293-307.
[http://dx.doi.org/10.1016/j.jmgm.2003.11.002 ] [PMID:  15177081] 
[10] 
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem.,  2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256 ] [PMID:  19399780] 
[11] 
Sanner, M.F. Python: a programming language for software integration and development. J. Mol. Graph. Model.,  1999, 17(1), 57-61.
[PMID:  10660911] 
[12] 
Morris, G.M.; Goodsell, D.S.; Halliday, R.S. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J. Comput. Chem.,  1998, 19(14), 1639-1662.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B] 
[13] 
Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Protein-ligand docking: current status and future challenges. Proteins,  2006, 65(1), 15-26.
[http://dx.doi.org/10.1002/prot.21082 ] [PMID:  16862531] 
[14] 
Lyne, P.D. Structure-based virtual screening: an overview. Drug Discov. Today,  2002, 7(20), 1047-1055.
[http://dx.doi.org/10.1016/S1359-6446(02)02483-2 ] [PMID:  12546894] 
[15] 
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with AutoDock: theory and practice. Expert Opin. Drug Discov.,  2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460 ] [PMID:  21532931] 
[16] 
Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model.,  2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+ ] [PMID:  15667143] 
[17] 
Morgunova, E.; Tuuttila, A.; Bergmann, U.; Isupov, M.; Lindqvist, Y.; Schneider, G.; Tryggvason, K. Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science,  1999, 284(5420), 1667-1670.
[http://dx.doi.org/10.1126/science.284.5420.1667 ] [PMID:  10356396] 
[18] 
Pronk, S.; Páll, S.; Schulz, R.; Larsson, P.; Bjelkmar, P.; Apostolov, R.; Shirts, M.R.; Smith, J.C.; Kasson, P.M.; van der Spoel, D.; Hess, B.; Lindahl, E. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics,  2013, 29(7), 845-854.
[http://dx.doi.org/10.1093/bioinformatics/btt055 ] [PMID:  23407358] 
[19] 
Oostenbrink, C.; Villa, A.; Mark, A.E.; van Gunsteren, W.F. A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J. Comput. Chem.,  2004, 25(13), 1656-1676.
[http://dx.doi.org/10.1002/jcc.20090 ] [PMID:  15264259] 
[20] 
Malde, A.K.; Zuo, L.; Breeze, M.; Stroet, M.; Poger, D.; Nair, P.C.; Oostenbrink, C.; Mark, A.E. An Automated force field Topology Builder (ATB) and repository: version 1.0. J. Chem. Theory Comput.,  2011, 7(12), 4026-4037.
[http://dx.doi.org/10.1021/ct200196m ] [PMID:  26598349] 
[21] 
Bussi, G.; Gervasio, F.L.; Laio, A.; Parrinello, M. Free-energy landscape for β hairpin folding from combined parallel tempering and metadynamics. J. Am. Chem. Soc.,  2006, 128(41), 13435-13441.
[http://dx.doi.org/10.1021/ja062463w ] [PMID:  17031956] 
[22] 
Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys.,  1981, 52(12), 7182-7190.
[http://dx.doi.org/10.1063/1.328693] 
[23] 
Essman, U.; Perera, L.; Berkowitz, M.L.; Darden, T.; Lee, H.; Pedersen, L.G. A smooth particle mesh Ewald method. J. Chem. Phys.,  1995, 103(19), 8577-8593.
[http://dx.doi.org/10.1063/1.470117] 
[24] 
Hess, B.; Bekker, H.; Berendsen, H.J.; Fraaije, J.G. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem.,  1997, 18(12), 1463-1472.
[http://dx.doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H] 
[25] 
Li, D.; Williams, J.I.; Pietras, R.J. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene,  2002, 21(18), 2805-2814.
[http://dx.doi.org/10.1038/sj.onc.1205410 ] [PMID:  11973639] 
[26] 
Cho, J.; Kim, Y. Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar. Biotechnol. (NY),  2002, 4(6), 521-525.
[http://dx.doi.org/10.1007/s10126-002-0064-3 ] [PMID:  14961226] 
[27] 
Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita, J.; Van Soest, R.W.; Fusetani, N. Ageladine A: an antiangiogenic matrixmetalloproteinase inhibitor from the marine sponge Agelas nakamurai. J. Am. Chem. Soc.,  2003, 125(51), 15700-15701.
[http://dx.doi.org/10.1021/ja038025w ] [PMID:  14677933] 
[28] 
Kim, S.; Han, J.; Lee, S.K.; Choi, M.Y.; Kim, J.; Lee, J.; Jung, S.P.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Lee, J.E.; Nam, S.J. Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-α in breast cancer cells. J. Surg. Res.,  2012, 176(1), e21-e29.
[http://dx.doi.org/10.1016/j.jss.2011.11.1041 ] [PMID:  22381172] 
[29] 
Kim, S.; Chung, J.H. Berberine prevents UV-induced MMP-1 and reduction of type I procollagen expression in human dermal fibroblasts. Phytomedicine,  2008, 15(9), 749-753.
[http://dx.doi.org/10.1016/j.phymed.2007.11.004 ] [PMID:  18164189] 
[30] 
Tanaka, K.; Hasegawa, J.; Asamitsu, K.; Okamoto, T. Magnolia ovovata extract and its active component magnolol prevent skin photoaging via inhibition of nuclear factor kappaB. Eur. J. Pharmacol.,  2007, 565(1-3), 212-219.
[http://dx.doi.org/10.1016/j.ejphar.2007.01.095 ] [PMID:  17346696] 
[31] 
Kim, K.R.; Park, K.K.; Chun, K.S.; Chung, W.Y. Honokiol inhibits the progression of collagen-induced arthritis by reducing levels of pro inflammatory cytokines and matrix metalloproteinases and blocking oxidative tissue damage. J. Pharmacol. Sci.,  2010, 114(1), 69-78.
[http://dx.doi.org/10.1254/jphs.10070FP ] [PMID:  20703013] 
[32] 
Ahmed, S.; Wang, N.; Lalonde, M.; Goldberg, V.M.; Haqqi, T.M. Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 β-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes. J. Pharmacol. Exp. Ther.,  2004, 308(2), 767-773.
[http://dx.doi.org/10.1124/jpet.103.059220 ] [PMID:  14600251] 
[33] 
Song, X.Z.; Xia, J.P.; Bi, Z.G. Effects of (-)-epigallocatechin-3-gallate on expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in fibroblasts irradiated with ultraviolet A. Chin. Med. J. (Engl.),  2004, 117(12), 1838-1841.
[PMID:  15603715] 
[34] 
Nakamuta, M.; Higashi, N.; Kohjima, M.; Fukushima, M.; Ohta, S.; Kotoh, K.; Kobayashi, N.; Enjoji, M. Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells. Int. J. Mol. Med.,  2005, 16(4), 677-681.
[PMID:  16142404] 
[35] 
Liu, Q.; Loo, W.T.; Sze, S.C.; Tong, Y. Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine,  2009, 16(10), 916-922.
[http://dx.doi.org/10.1016/j.phymed.2009.04.008 ] [PMID:  19524420] 
[36] 
Hwang, B.M.; Noh, E.M.; Kim, J.S.; Kim, J.M.; You, Y.O.; Hwang, J.K.; Kwon, K.B.; Lee, Y.R. Curcumin inhibits UVB induced matrix metalloproteinase-1/3 expression by suppressing the MAPK-p38/JNK pathways in human dermal fibroblasts. Exp. Dermatol.,  2013, 22(5), 371-374.
[http://dx.doi.org/10.1111/exd.12137 ] [PMID:  23614750] 
[37] 
Leu, S.J.; Lin, Y.P.; Lin, R.D.; Wen, C.L.; Cheng, K.T.; Hsu, F.L.; Lee, M.H. Phenolic constituents of Malus doumeri var. formosana in the field of skin care. Biol. Pharm. Bull.,  2006, 29(4), 740-745.
[http://dx.doi.org/10.1248/bpb.29.740 ] [PMID:  16595910] 
[38] 
Lim, H.; Kim, H.P. Inhibition of mammalian collagenase, matrix metalloproteinase-1, by naturally-occurring flavonoids. Planta Med.,  2007, 73(12), 1267-1274.
[http://dx.doi.org/10.1055/s-2007-990220 ] [PMID:  17886198] 
[39] 
Hwang, Y.P.; Oh, K.N.; Yun, H.J.; Jeong, H.G. The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cells. J. Dermatol. Sci.,  2011, 61(1), 23-31.
[http://dx.doi.org/10.1016/j.jdermsci.2010.10.016 ] [PMID:  21112745] 
[40] 
Sato, T.; Koike, L.; Miyata, Y.; Hirata, M.; Mimaki, Y.; Sashida, Y.; Yano, M.; Ito, A. Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res.,  2002, 62(4), 1025-1029.
[PMID:  11861377] 
[41] 
Ho, J.N.; Lee, Y.H.; Park, J.S.; Jun, W.J.; Kim, H.K.; Hong, B.S.; Shin, D.H.; Cho, H.Y. Protective effects of aucubin isolated from Eucommia ulmoides against UVB-induced oxidative stress in human skin fibroblasts. Biol. Pharm. Bull.,  2005, 28(7), 1244-1248.
[http://dx.doi.org/10.1248/bpb.28.1244 ] [PMID:  15997107] 
[42] 
Oh, H.I.; Shim, J.S.; Gwon, S.H.; Kwon, H.J.; Hwang, J.K. The effect of xanthorrhizol on the expression of matrix metalloproteinase-1 and type-I procollagen in ultraviolet-irradiated human skin fibroblasts. Phytother. Res.,  2009, 23(9), 1299-1302.
[http://dx.doi.org/10.1002/ptr.2768 ] [PMID:  19277961] 
[43] 
Yang, B.; Ji, C.; Kang, J.; Chen, W.; Bi, Z.; Wan, Y. Trans-Zeatin inhibits UVB-induced matrix metalloproteinase-1 expression via MAP kinase signaling in human skin fibroblasts. Int. J. Mol. Med.,  2009, 23(4), 555-560.
[PMID:  19288033] 
[44] 
Joe, M.J.; Kim, S.N.; Choi, H.Y.; Shin, W.S.; Park, G.M.; Kang, D.W.; Kim, Y.K. The inhibitory effects of eckol and dieckol from Ecklonia stolonifera on the expression of matrix metalloproteinase-1 in human dermal fibroblasts. Biol. Pharm. Bull.,  2006, 29(8), 1735-1739.
[http://dx.doi.org/10.1248/bpb.29.1735 ] [PMID:  16880634] 
[45] 
Elliott, S.; Rowan, A.D.; Carrère, S.; Koshy, P.; Catterall, J.B.; Cawston, T.E. Esculetin inhibits cartilage resorption induced by interleukin 1α in combination with oncostatin M. Ann. Rheum. Dis.,  2001, 60(2), 158-165.
[http://dx.doi.org/10.1136/ard.60.2.158 ] [PMID:  11156550] 
[46] 
Zhang, C.; Kim, S.K. Matrix metalloproteinase inhibitors (MMPIs) from marine natural products: the current situation and future prospects. Mar. Drugs,  2009, 7(2), 71-84.
[http://dx.doi.org/10.3390/md7020071 ] [PMID:  19597572] 
[47] 
Kim, K.H.; Kim, N.D.; Seong, B.L. Pharmacophore-based virtual screening: a review of recent applications. Expert Opin. Drug Discov.,  2010, 5(3), 205-222.
[http://dx.doi.org/10.1517/17460441003592072 ] [PMID:  22823018] 
[48] 
Singh, G.G.; McKechnie, I.; Braje, T.J.; Campbell, B. All models are wrong but some are useful: A response to Campbell’s comment on estimating Mytilus californianus shell size. J. Archaeol. Sci.,  2015, 2015(63), 160-163.
[http://dx.doi.org/10.1016/j.jas.2015.08.021] 
[49] 
Liao, K.H.; Chen, K.B.; Lee, W.Y.; Sun, M.F.; Lee, C.C.; Chen, C.Y.C. Ligand-based and structure-based investigation for Alzheimer’s disease from traditional chinese medicine. Evid. Based Complement. Alternat. Med.,  2014, 2014, 364819.
[http://dx.doi.org/10.1155/2014/364819 ] [PMID:  24899907] 
[50] 
Bhardwaj, A.; Leelavathi, S.; Mazumdar-Leighton, S.; Ghosh, A.; Ramakumar, S.; Reddy, V.S. The critical role of N- and C-terminal contact in protein stability and folding of a family 10 xylanase under extreme conditions. PLoS One,  2010, 5(6), e11347.
[http://dx.doi.org/10.1371/journal.pone.0011347 ] [PMID:  20596542] 

Rights & Permissions Print Cite

Article Metrics

28

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207323666200428114216	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Scaffold-based Screening and Molecular Dynamics Simulation Study to Identify Two Structurally Related Phenolic Compounds as Potent MMP1 Inhibitors

Abstract Play Pause

Related Journals

Related Articles

Abstract