title: Retrospective molecular docking study of WY-25105 ligand to β-secretase and bias of the three-dimensional structure flexibility.
abstract: β-Secretase (BACE) is a very promising target in the search for a treatment for Alzheimer's disease using a protein-ligand inhibition approach. Given the many published X-ray structures of BACE protein, structure-based drug design has been used extensively to support new inhibitor discovery programs. Due to the high flexibility and large catalytic site of this protein, sampling of the huge conformational space of the binding site is the big challenge to overcome and is the main limitation of the most widely used docking programs. Incorrect treatment of these pitfalls can introduce bias into ligand docking and could affect the results. This is especially the case with the WY-25105 compound reported by the Wyeth Corporation as a BACE ligand that did not fit into any of the known crystal structures. In the present retrospective study, a set of available X-ray enzyme structures was selected and molecular dynamics simulations were conducted to generate more diverse representative BACE protein conformations. These conformations were then used for a docking study of the WY-25105 compound. The results confirmed the need to use an ensemble of structures in protein-ligand docking for identification of new binding modes in structure-based drug design of BACE inhibitors.
authors.affiliation: Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Leo
authors.initials: L
authors.lastname: Ghemtio
authors.forename: Nicolas
authors.initials: N
authors.lastname: Muzet
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006146:Guanidines / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018697:Nootropic Agents / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D008024:Ligands; D018697:Nootropic Agents; D011758:Pyrroles; C586188:WY-25105; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Mol Biol. 1995 Jan 6;245(1):43-53
references.pmid: 7823319
references.citation: J Med Chem. 2005 Jun 2;48(11):3749-55
references.pmid: 15916426
references.citation: J Neurochem. 2010 Feb;112(4):1045-53
references.pmid: 19968762
references.citation: Biochemistry. 2005 Jan 11;44(1):105-12
references.pmid: 15628850
references.citation: J Med Chem. 2007 Sep 6;50(18):4261-4
references.pmid: 17685503
references.citation: Proteins. 2011 Jul;79(7):2247-59
references.pmid: 21590744
references.citation: J Med Chem. 2001 Aug 30;44(18):2865-8
references.pmid: 11520194
references.citation: J Chem Inf Model. 2009 Nov;49(11):2564-71
references.pmid: 19928836
references.citation: Proteins. 2010 May 1;78(6):1575-82
references.pmid: 20112416
references.citation: Curr Opin Drug Discov Devel. 2004 Jul;7(4):536-56
references.pmid: 15338962
references.citation: J Med Chem. 2004 Oct 7;47(21):5159-66
references.pmid: 15456259
references.citation: Front Biosci (Landmark Ed). 2011 Jun 01;16:2289-306
references.pmid: 21622177
references.citation: Structure. 2005 Oct;13(10):1487-98
references.pmid: 16216580
references.citation: Acta Pharmacol Sin. 2004 Jun;25(6):705-13
references.pmid: 15169620
references.citation: Chem Biol Drug Des. 2011 Aug;78(2):252-9
references.pmid: 21585710
references.citation: Recent Pat CNS Drug Discov. 2011 May 1;6(2):91-106
references.pmid: 21585329
references.citation: Bioorg Med Chem Lett. 2007 Oct 1;17(19):5353-6
references.pmid: 17761418
references.citation: J Mol Biol. 1997 Apr 4;267(3):727-48
references.pmid: 9126849
references.citation: Mol Inform. 2010 Mar 15;29(3):176-87
references.pmid: 27462761
references.citation: J Comput Chem. 2011 Dec;32(16):3433-9
references.pmid: 21919015
references.citation: J Med Chem. 2002 Jan 31;45(3):541-58
references.pmid: 11806706
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7354-9
references.pmid: 12777627
references.citation: Nat Rev Neurol. 2010 Feb;6(2):99-107
references.pmid: 20139999
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):178-84
references.pmid: 18302984
references.citation: J Mol Biol. 2004 Oct 15;343(2):407-16
references.pmid: 15451669
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: Acta Pharmacol Sin. 2006 Dec;27(12):1586-93
references.pmid: 17112413
references.citation: J Med Chem. 2006 Feb 9;49(3):839-42
references.pmid: 16451048
references.citation: Biochemistry. 2010 Aug 31;49(34):7255-63
references.pmid: 20687525
references.citation: Curr Opin Struct Biol. 2009 Apr;19(2):120-7
references.pmid: 19361980
references.citation: Bioorg Med Chem Lett. 2010 Mar 15;20(6):1924-7
references.pmid: 20172717
references.citation: J Med Chem. 2001 Jun 21;44(13):2039-60
references.pmid: 11405641
references.citation: Expert Opin Drug Discov. 2007 Aug;2(8):1129-38
references.pmid: 23484877
references.citation: J Neurochem. 2012 Jan;120 Suppl 1:71-83
references.pmid: 22122681
references.citation: Curr Comput Aided Drug Des. 2011 Jun;7(2):146-57
references.pmid: 21534921
references.citation: Bioorg Med Chem Lett. 2011 Apr 1;21(7):1942-7
references.pmid: 21388807
references.citation: J Med Chem. 2004 Dec 2;47(25):6117-9
references.pmid: 15566281
references.citation: Methods Mol Biol. 2007;400:89-102
references.pmid: 17951729
references.citation: Biophys J. 2010 Jul 7;99(1):218-26
references.pmid: 20655850
references.citation: Bioorg Med Chem Lett. 2010 Nov 15;20(22):6533-7
references.pmid: 20937559
references.citation: Int J Biochem Cell Biol. 2010 Dec;42(12):1923-6
references.pmid: 20817005
references.citation: J Med Chem. 2004 Jun 3;47(12):3032-47
references.pmid: 15163185
references.citation: Int J Mol Sci. 2010 Aug 18;11(8):3016-34
references.pmid: 21152288
references.citation: Biochemistry. 2011 Jul 19;50(28):6157-69
references.pmid: 21678954
references.citation: J Med Chem. 2006 Oct 19;49(21):6158-61
references.pmid: 17034121
references.citation: Bioorg Med Chem Lett. 2006 Feb;16(3):641-4
references.pmid: 16263281
references.citation: Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712
references.pmid: 21852788
references.citation: Nat Chem Biol. 2009 May;5(5):274-5
references.pmid: 19377449
references.citation: J Med Chem. 2010 Feb 11;53(3):942-50
references.pmid: 20043700
references.citation: J Am Chem Soc. 2005 Mar 23;127(11):3734-42
references.pmid: 15771507
references.citation: J Biol Chem. 2004 Sep 24;279(39):40252-4
references.pmid: 15299032
references.citation: J Neurosci. 2009 Oct 14;29(41):12787-94
references.pmid: 19828790
references.citation: Biochemistry. 2004 Apr 27;43(16):4689-95
references.pmid: 15096037
references.citation: Science. 2000 Oct 6;290(5489):150-3
references.pmid: 11021803