title: Combined structure- and ligand-based pharmacophore modeling and molecular dynamics simulation studies to identify selective inhibitors of MMP-8.
abstract: Matrix metalloproteinase-8 (MMP-8) is the key mediator in initiating type I collagen degradation and is associated with rheumatoid arthritis. In the present study, a pharmacophore hypothesis was developed based on selective non zinc binding inhibitors of MMP-8. The pharmacophore hypothesis was refined manually and validated by observing structures and the interactions of MMP-8 inhibitors. The refined pharmacophore model was able to discriminate the non-zinc binding inhibitors of MMP-8 with respect to other inhibitors. Hence this study proposes a combined structure- and ligand-based pharmacophore model that is suitable for retrieving the novel inhibitors of MMP-8. The pharmacophore hypothesis AADRH was used as query for retrieving potential compounds from the Zinc database and hits were selected based on the catalytic selective amino acid residues of Arg 222, and Tyr 227. We identified six compounds as potent inhibitors and their selectivity profile were checked against different subtypes of MMPs using the cross-docking method. Molecular dynamics results indicated that ZINC 00673680 forms a stable interaction with the key amino acid residues and avoids the zinc atom with a distance of 5.49 Å. Our computational study might be useful for further development of selective MMP-8 inhibitors.
authors.affiliation: Department of Bioinformatics, SRM University, SRM Nagar, Kattankulathur, 603 203, Kancheepuram District, Chennai, India.
authors.forename: Sukesh
authors.initials: S
authors.lastname: Kalva
authors.forename: D
authors.initials: D
authors.lastname: Vinod
authors.forename: Lilly M
authors.initials: LM
authors.lastname: Saleena
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D062126:Databases, Chemical; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020784:Matrix Metalloproteinase 8; D015032:Zinc
references.citation: Eur J Med Chem. 2012 Jan;47(1):143-52
references.pmid: 22088955
references.citation: Eur J Pharmacol. 2010 Oct 10;644(1-3):138-45
references.pmid: 20619256
references.citation: Nature. 2003 May 15;423(6937):356-61
references.pmid: 12748655
references.citation: Trends Pharmacol Sci. 2013 Apr;34(4):233-42
references.pmid: 23541335
references.citation: Bioorg Med Chem Lett. 2008 Feb 1;18(3):1135-9
references.pmid: 18086526
references.citation: Bioorg Med Chem. 2009 Feb 1;17(3):990-1005
references.pmid: 18358729
references.citation: J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):647-71
references.pmid: 17124629
references.citation: Eur J Med Chem. 2008 May;43(5):1008-14
references.pmid: 17719700
references.citation: Clin Calcium. 2012 Feb;22(2):179-85
references.pmid: 22298070
references.citation: Bioorg Med Chem Lett. 2005 Sep 15;15(18):4105-9
references.pmid: 16005220
references.citation: J Med Chem. 2000 Feb 10;43(3):369-80
references.pmid: 10669564
references.citation: J Mol Graph Model. 2013 Jul;44:297-310
references.pmid: 23938376
references.citation: J Mol Biol. 2013 May 27;425(10):1815-25
references.pmid: 23399546
references.citation: Bioorg Med Chem. 2005 Aug 1;13(15):4740-9
references.pmid: 15935680
references.citation: J Neurosci. 2010 Nov 17;30(46):15337-57
references.pmid: 21084591
references.citation: Pharmacol Res. 2011 Feb;63(2):108-13
references.pmid: 20937384
references.citation: J Chem Inf Model. 2007 Nov-Dec;47(6):2416-28
references.pmid: 17949071
references.citation: J Med Chem. 2007 Nov 15;50(23):5752-64
references.pmid: 17956082
references.citation: Mol Cell Biochem. 2003 Nov;253(1-2):31-40
references.pmid: 14619953
references.citation: J Clin Periodontol. 2010 Dec;37(12):1068-74
references.pmid: 20880053
references.citation: Bioorg Med Chem. 2002 Nov;10(11):3529-44
references.pmid: 12213468
references.citation: Arthritis Res Ther. 2010;12(6):R224
references.pmid: 21190566
references.citation: J Med Chem. 2001 Sep 13;44(19):3074-82
references.pmid: 11543676
references.citation: Curr Top Med Chem. 2013;13(6):705-11
references.pmid: 23574519
references.citation: Nature. 2002 Dec 19-26;420(6917):846-52
references.pmid: 12490957
references.citation: Eur J Med Chem. 2011 Jul;46(7):2617-29
references.pmid: 21514700
references.citation: Bioorg Med Chem Lett. 2001 Apr 23;11(8):1009-13
references.pmid: 11327577
references.citation: Bioinformation. 2012;8(7):301-8
references.pmid: 22553386
references.citation: J Comput Aided Mol Des. 2012 Mar;26(3):267-77
references.pmid: 22218727
references.citation: Am J Pathol. 2008 Jul;173(1):144-53
references.pmid: 18556780
references.citation: J Comput Chem. 2011 Oct;32(13):2800-9
references.pmid: 21717478
references.citation: Curr Med Chem. 2008;15(22):2192-222
references.pmid: 18781944
references.citation: J Comput Aided Mol Des. 2008 Mar-Apr;22(3-4):169-78
references.pmid: 18188508
references.citation: J Med Chem. 2000 Jan 27;43(2):156-66
references.pmid: 10649971
references.citation: Drug Metab Pharmacokinet. 2004 Oct;19(5):327-38
references.pmid: 15548844
references.citation: Circ Res. 2003 May 2;92(8):827-39
references.pmid: 12730128
references.citation: J Med Chem. 2009 Feb 26;52(4):1040-9
references.pmid: 19173605
references.citation: J Mol Graph Model. 2013 Jul;44:44-53
references.pmid: 23732305
references.citation: Eur J Cancer. 2003 Nov;39(17):2499-505
references.pmid: 14602136
references.citation: J Chem Theory Comput. 2013 Feb 12;9(2):1282-93
references.pmid: 26588769
references.citation: J Med Chem. 2008 Dec 25;51(24):7968-79
references.pmid: 19053764
references.citation: J Med Chem. 2004 Jun 3;47(12):3065-74
references.pmid: 15163188
references.citation: Drug Discov Today. 2007 Aug;12(15-16):640-6
references.pmid: 17706545