title: Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.
abstract: Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. The sequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and nucleotide at the +1 position of the cleavage site was the major (favorable) contributor to the total binding energy. Mechanistic insights gained by a potential of mean force analysis implicated that the drug dissociation step was associated with the sequence selectivity. Pharmaceutical insights gained by our molecular dynamics analyses explained why LMP-776, an indenoisoquinoline derivative under clinical development at the National Institutes of Health, displays different sequence selectivity when compared with camptothecin and its clinical derivatives.
authors.affiliation: Center for High Performance Computing, Institute of Advanced Computing and Digital Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Boulevard, University Town of Shenzhen, Xili Nanshan, Shenzhen 518055, China, Department of Chemistry and Institutes of Molecular Technology for Drug Discovery and Synthesis, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Fung-Ming
authors.initials: FM
authors.lastname: Siu
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D001483:Base Sequence; D002166:Camptothecin / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D053837:DNA Cleavage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
references.citation: Nucleic Acids Res. 2008 Oct;36(17):5635-44
references.pmid: 18772225
references.citation: Nucleic Acids Res. 1988 Dec 9;16(23):11157-70
references.pmid: 2849758
references.citation: J Am Chem Soc. 2005 Jul 20;127(28):9960-1
references.pmid: 16011334
references.citation: J Med Chem. 2005 Apr 7;48(7):2336-45
references.pmid: 15801827
references.citation: Drug Resist Updat. 1999 Oct;2(5):307-318
references.pmid: 11504505
references.citation: Nucleic Acids Res. 2008 Apr;36(7):2301-10
references.pmid: 18292117
references.citation: Cancer Res. 2007 Nov 1;67(21):10397-405
references.pmid: 17974983
references.citation: J Biol Chem. 2007 Mar 30;282(13):9855-9864
references.pmid: 17276985
references.citation: J Biol Chem. 1999 Nov 12;274(46):32950-60
references.pmid: 10551862
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92
references.pmid: 12426403
references.citation: Biochemistry. 2012 Jan 10;51(1):43-51
references.pmid: 22124209
references.citation: Proteins. 2004 May 1;55(2):383-94
references.pmid: 15048829
references.citation: Cancer Res. 2003 Nov 1;63(21):7428-35
references.pmid: 14612542
references.citation: Chem Biol. 2010 May 28;17(5):421-33
references.pmid: 20534341
references.citation: J Nat Prod. 2011 Jun 24;74(6):1401-7
references.pmid: 21542600
references.citation: J Natl Cancer Inst. 1994 Jun 1;86(11):836-42
references.pmid: 8182764
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: J Comput Chem. 2005 Dec;26(16):1668-88
references.pmid: 16200636
references.citation: J Am Chem Soc. 2008 Dec 31;130(52):17928-37
references.pmid: 19035632
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6782-6
references.pmid: 18443285
references.citation: Int J Cancer. 1998 Jan 5;75(1):145-50
references.pmid: 9426703
references.citation: Nucleic Acids Res. 2008 Oct;36(17):5645-51
references.pmid: 18765473
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W679-85
references.pmid: 15215475
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Med Chem. 2005 Jun 2;48(11):3796-807
references.pmid: 15916431
references.citation: J Mol Biol. 1997 Jun 13;269(3):355-72
references.pmid: 9199405
references.citation: Amino Acids. 2011 Oct;41(4):945-53
references.pmid: 21046176
references.citation: Biochemistry. 2010 May 4;49(17):3575-92
references.pmid: 20230061
references.citation: Mol Cancer. 2011 May 27;10:64
references.pmid: 21619602
references.citation: J Biol Chem. 2003 Oct 31;278(44):43268-75
references.pmid: 12904303
references.citation: PLoS One. 2010 Jun 03;5(6):e10934
references.pmid: 20532182
references.citation: Biophys J. 2007 Jun 1;92(11):3817-29
references.pmid: 17351000
references.citation: Nucleic Acids Res. 2012 May;40(9):3812-21
references.pmid: 22241779
references.citation: Biochemistry. 2009 Sep 8;48(35):8435-48
references.pmid: 19627157
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2002 Mar;65(3 Pt 1):031910
references.pmid: 11909112
references.citation: Nucleic Acids Res. 2008 Apr;36(7):2379-94
references.pmid: 18299282
references.citation: Mol Cancer Ther. 2009 May;8(5):1008-14
references.pmid: 19383846
references.citation: Biochemistry. 1999 Apr 6;38(14):4374-81
references.pmid: 10194356
references.citation: J Am Chem Soc. 2005 Nov 9;127(44):15429-36
references.pmid: 16262406
references.citation: Cancer Res. 2010 Oct 15;70(20):8055-65
references.pmid: 20817775
references.citation: J Mol Biol. 1992 Dec 20;228(4):1025-30
references.pmid: 1335513
references.citation: Science. 1998 Mar 6;279(5356):1504-13
references.pmid: 9488644
references.citation: PLoS One. 2011;6(8):e24314
references.pmid: 21912628
references.citation: Nucleic Acids Res. 2005 Jun 08;33(10):3339-50
references.pmid: 15944452
references.citation: Nucleic Acids Res. 2009 Nov;37(20):6849-58
references.pmid: 19767617
references.citation: J Mol Biol. 1988 Jul 20;202(2):333-42
references.pmid: 2845097
references.citation: Anticancer Drugs. 1997 Apr;8(4):336-44
references.pmid: 9180386
references.citation: Biophys J. 2004 Dec;87(6):4087-97
references.pmid: 15347588
references.citation: Chem Biol. 2001 Sep;8(9):871-81
references.pmid: 11564555
references.citation: Cancer Res. 1997 Apr 15;57(8):1516-22
references.pmid: 9108454
references.citation: Biochem J. 2008 May 1;411(3):523-30
references.pmid: 18215123
references.citation: J Mol Biol. 2003 Jul 18;330(4):891-913
references.pmid: 12850155
references.citation: Nucleic Acids Res. 1989 Nov 11;17(21):8521-32
references.pmid: 2555774
references.citation: Proteins. 2007 Jun 1;67(4):1026-47
references.pmid: 17377991
references.citation: Biochemistry. 2000 Jun 13;39(23):6832-40
references.pmid: 10841763
references.citation: J Biol Chem. 1991 Oct 25;266(30):20418-23
references.pmid: 1657924
references.citation: Biopolymers. 2012 Feb;97(2):134-44
references.pmid: 21898362
references.citation: Mol Immunol. 2010 Feb;47(5):982-90
references.pmid: 20022377
references.citation: Biochemistry. 2005 Mar 22;44(11):4171-80
references.pmid: 15766244
references.citation: PLoS One. 2011;6(9):e25150
references.pmid: 21966440
references.citation: FASEB J. 2010 Jul;24(7):2235-44
references.pmid: 20179147
references.citation: Cancer Res. 1995 Mar 15;55(6):1339-46
references.pmid: 7882333
references.citation: J Mol Biol. 2008 Feb 29;376(4):1201-14
references.pmid: 18206907
references.citation: Biochemistry. 1995 May 30;34(21):7200-6
references.pmid: 7766631
references.citation: Nucleic Acids Res. 2003 Dec 15;31(24):7255-63
references.pmid: 14654701
references.citation: Biochem Pharmacol. 2008 Mar 15;75(6):1262-71
references.pmid: 18061144
references.citation: PLoS One. 2013 May 29;8(5):e64886
references.pmid: 23734224
references.citation: J Mol Model. 2007 Mar;13(3):393-400
references.pmid: 17072654
references.citation: Nat Rev Drug Discov. 2011 Dec 16;11(1):25-36
references.pmid: 22173432
references.citation: Nucleic Acids Res. 2010 Jan;38(1):159-71
references.pmid: 19854946
references.citation: J Mol Biol. 1999 Sep 24;292(3):685-96
references.pmid: 10497031
references.citation: J Mol Biol. 2004 Feb 6;336(1):93-103
references.pmid: 14741206
references.citation: Biochim Biophys Acta. 2010 Dec;1806(2):240-50
references.pmid: 20600630