title: Structure-based DNA-targeting strategies with small molecule ligands for drug discovery.
abstract: Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics.
authors: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors: Jia
authors: J
authors: Sheng
authors: Jianhua
authors: J
authors: Gan
authors: Zhen
authors: Z
authors: Huang
mesh_terms: D000818:Animals; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D008024:Ligands; D009690:Nucleic Acid Conformation; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D007364:Intercalating Agents; D008024:Ligands; D054852:Small Molecule Libraries; D004247:DNA
keywords: modification and derivatization; nucleic acids; small molecule ligands; structure-based drug discovery; structures of DNA-ligand complexes
references: EMBO J. 2004 Jul 7;23(13):2498-509
references: 15192705
references: Nat Struct Biol. 2002 Jan;9(1):57-60
references: 11731803
references: J Inorg Biochem. 2010 Sep;104(9):902-8
references: 20541266
references: J Mol Biol. 1995 Mar 24;247(2):338-59
references: 7707379
references: Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):417-24
references: 16552143
references: J Mol Biol. 2001 Apr 20;308(1):15-26
references: 11302703
references: Nucleic Acids Res. 1998 Dec 1;26(23):5464-71
references: 9826773
references: Biochemistry. 1997 Apr 22;36(16):4792-9
references: 9125500
references: Biochemistry. 2008 Jul 8;47(27):7147-57
references: 18549246
references: Biochemistry. 2003 Jul 22;42(28):8472-83
references: 12859193
references: Angew Chem Int Ed Engl. 2006 Feb 13;45(8):1227-31
references: 16463312
references: Biochemistry. 2006 Aug 29;45(34):10217-32
references: 16922497
references: Semin Oncol. 1992 Dec;19(6):670-86
references: 1462166
references: Curr Opin Struct Biol. 2010 Jun;20(3):262-75
references: 20381338
references: Org Biomol Chem. 2010 Jul 21;8(14):3179-87
references: 20490406
references: J Biomol Struct Dyn. 2004 Apr;21(5):713-24
references: 14769064
references: Nature. 1995 Oct 19;377(6550):649-52
references: 7566180
references: N Engl J Med. 1999 Apr 15;340(15):1144-53
references: 10202165
references: J Am Chem Soc. 2011 Oct 12;133(40):16101-10
references: 21916419
references: Curr Top Med Chem. 2002 Mar;2(3):247-69
references: 11944819
references: Curr Opin Struct Biol. 2009 Jun;19(3):239-50
references: 19487118
references: Chem Soc Rev. 2011 Sep;40(9):4591-602
references: 21666919
references: J Med Chem. 2004 Apr 22;47(9):2296-307
references: 15084128
references: Biochemistry. 1992 Aug 11;31(31):7104-9
references: 1643044
references: Nucleic Acids Res. 2009 Sep;37(16):5550-8
references: 19578063
references: J Am Chem Soc. 2003 Jul 9;125(27):8070-1
references: 12837054
references: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):429-34
references: 17194756
references: Nucleosides Nucleotides Nucleic Acids. 2001 Sep;20(9):1723-34
references: 11580197
references: Chem Biodivers. 2008 Mar;5(3):396-407
references: 18357549
references: Bioorg Med Chem Lett. 2003 May 5;13(9):1565-70
references: 12699756
references: Science. 2002 May 17;296(5571):1260-3
references: 12016301
references: Org Lett. 2007 Mar 1;9(5):749-52
references: 17263541
references: J Nucleic Acids. 2010 Oct 07;2010:107289
references: 20976303
references: ACS Chem Biol. 2012 Jan 20;7(1):218-25
references: 22004017
references: J Mol Biol. 2005 Jun 17;349(4):731-44
references: 15896803
references: Acta Crystallogr D Biol Crystallogr. 1999 Mar;55(Pt 3):602-9
references: 10089456
references: Science. 1987 Oct 30;238(4827):645-50
references: 3118463
references: Biochimie. 2008 Jul;90(7):999-1014
references: 18343228
references: Chem Soc Rev. 2007 Mar;36(3):471-83
references: 17325786
references: Chem Res Toxicol. 2008 Jul;21(7):1348-58
references: 18549249
references: Biochimie. 2008 Aug;90(8):1117-30
references: 18331847
references: Mutat Res. 2007 Oct 1;623(1-2):72-82
references: 17434187
references: Bioorg Med Chem. 1995 Jun;3(6):795-809
references: 7582957
references: Nucleic Acids Res. 1987 Oct 12;15(19):7749-60
references: 3671065
references: Proc Natl Acad Sci U S A. 1989 Jan;86(2):462-5
references: 2492107
references: Prog Nucleic Acid Res Mol Biol. 1975;15(0):285-318
references: 1094496
references: J Biol Chem. 1974 Nov 10;249(21):6719-31
references: 4371420
references: Cell. 1995 Jun 30;81(7):991-1002
references: 7541315
references: Science. 2009 Apr 17;324(5925):407-10
references: 19372434
references: Carcinogenesis. 1982;3(6):723-5
references: 6811145
references: Biochemistry. 2009 Dec 29;48(51):12223-32
references: 19911838
references: Nature. 1999 Jun 17;399(6737):708-12
references: 10385126
references: Biochemistry. 1995 Jan 10;34(1):40-9
references: 7819222
references: Biochemistry. 2010 Jul 27;49(29):6155-64
references: 20604523
references: Nat Struct Biol. 1999 Oct;6(10):913-7
references: 10504723
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: Biochemistry. 2010 Jan 26;49(3):452-69
references: 20000367
references: Chem Res Toxicol. 2009 Nov;22(11):1810-6
references: 19916525
references: Science. 1984 Sep 14;225(4667):1115-21
references: 6474168
references: Curr Opin Mol Ther. 2010 Apr;12(2):184-91
references: 20373262
references: Biochemistry. 1999 Dec 7;38(49):16067-75
references: 10587429
references: J Biomol Struct Dyn. 1984 Mar;1(5):1133-47
references: 6101078
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4758-63
references: 15037741
references: Angew Chem Int Ed Engl. 2010 Apr 12;49(17):3077-80
references: 20333640
references: J Am Chem Soc. 2004 Jun 30;126(25):7958-66
references: 15212545
references: Nucleic Acids Res. 2005 Aug 26;33(15):4838-48
references: 16126848
references: J Med Chem. 2002 Jan 31;45(3):590-7
references: 11806711
references: Pharmacol Res. 2004 Aug;50(2):201-7
references: 15177310
references: J Med Chem. 1987 Nov;30(11):2074-80
references: 3669015
references: Mutat Res. 2005 Mar;589(2):111-35
references: 15795165
references: Biochemistry. 1998 Apr 14;37(15):5136-46
references: 9548744
references: Nat Struct Biol. 1998 Feb;5(2):104-9
references: 9461074
references: Biochemistry. 1998 Sep 8;37(36):12367-74
references: 9730808
references: N Engl J Med. 1999 Apr 15;340(15):1154-61
references: 10202166
references: Acc Chem Res. 2009 Jan 20;42(1):11-21
references: 18798655
references: Biochemistry. 2001 Sep 4;40(35):10473-84
references: 11523988
references: J Am Chem Soc. 2008 May 28;130(21):6859-66
references: 18459783
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10418-23
references: 17566103
references: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13039-44
references: 18753620
references: Science. 1993 Sep 3;261(5126):1319-21
references: 8362243
references: Chem Rev. 2006 Feb;106(2):277-301
references: 16464006
references: Biochemistry. 1999 Dec 21;38(51):16810-5
references: 10606513
references: Biochemistry. 2007 Apr 24;46(16):4793-803
references: 17388570
references: Science. 1998 Oct 2;282(5386):111-5
references: 9756473
references: J Mol Recognit. 2004 Jul-Aug;17(4):277-85
references: 15227636
references: Nature. 1994 Nov 3;372(6501):68-74
references: 7969422
references: Biochemistry. 1990 Mar 13;29(10):2538-49
references: 2334681
references: Inorg Chem. 2008 Nov 17;47(22):10626-33
references: 18947179
references: Carcinogenesis. 1997 Jul;18(7):1291-7
references: 9230270
references: J Med Chem. 1980 Dec;23(12):1336-43
references: 7452686
references: Biochemistry. 1988 Mar 8;27(5):1744-51
references: 3365421
references: Nature. 2005 Apr 14;434(7035):913-7
references: 15829966
references: Nucleic Acids Res. 1999 Jul 1;27(13):2691-8
references: 10373586
references: Cancer Cell. 2007 May;11(5):431-45
references: 17482133
references: Mutat Res. 2005 Oct 15;578(1-2):88-99
references: 15990125
references: Bioconjug Chem. 1991 Nov-Dec;2(6):379-93
references: 1666838
references: Proc Natl Acad Sci U S A. 1989 Sep;86(17):6557-61
references: 2671994
references: Trends Biotechnol. 2006 Dec;24(12):563-70
references: 17045686
references: Biochemistry. 1996 Apr 16;35(15):5041-53
references: 8664297
references: Science. 1982 Dec 10;218(4577):1075-82
references: 6890712
references: Anticancer Drug Des. 1990 Feb;5(1):43-53
references: 2180423
references: Angew Chem Int Ed Engl. 2007;46(21):3850-4
references: 17477457
references: Annu Rev Biophys Biomol Struct. 2007;36:281-305
references: 17288535
references: Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6706-10
references: 1386670
references: J Med Chem. 2007 Jul 26;50(15):3403-11
references: 17602547
references: J Mol Biol. 1991 Nov 20;222(2):167-77
references: 1960720
references: Chem Biodivers. 2010 Apr;7(4):753-85
references: 20397215
references: Chem Commun (Camb). 2002 Jan 7;(1):70-1
references: 12120315
references: Nucleic Acids Res. 1992 Sep 25;20(18):4889-95
references: 1408804
references: J Mol Biol. 1987 Sep 20;197(2):257-71
references: 2445998
references: Nat Rev Genet. 2001 Dec;2(12):919-29
references: 11733745
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4534-8
references: 8183944
references: Nucleic Acids Res. 2004 Mar 08;32(5):1638-46
references: 15007109
references: J Am Chem Soc. 2006 Aug 9;128(31):10085-95
references: 16881637
references: Nat Struct Mol Biol. 2005 Mar;12(3):218-24
references: 15723077
references: Biochemistry. 1999 Jan 5;38(1):199-206
references: 9890899
references: Proc Natl Acad Sci U S A. 2004 May 4;101(18):6864-9
references: 15100411
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2672-7
references: 11854467
references: Science. 1996 Jun 28;272(5270):1943-6
references: 8658168
references: J Am Chem Soc. 2003 Apr 9;125(14):4066-7
references: 12670225
references: N Engl J Med. 1999 Apr 15;340(15):1137-43
references: 10202164
references: Eur J Med Chem. 2007 Jun;42(6):752-71
references: 17433851
references: J Biomol Struct Dyn. 2000 Apr;17(5):887-901
references: 10798533
references: Annu Rev Biochem. 1981;50:159-92
references: 6168236
references: Biochemistry. 1987 Feb 24;26(4):1152-63
references: 3567161
references: FEBS Lett. 1991 Apr 9;281(1-2):9-19
references: 1849843
references: Angew Chem Int Ed Engl. 2006 May 12;45(20):3310-4
references: 16596680
references: Biochemistry. 2002 Apr 23;41(16):5131-43
references: 11955061
references: Dalton Trans. 2009 Jan 21;(3):399-414
references: 19122895
references: FASEB J. 1998 Jul;12(10):791-9
references: 9657519
references: Chem Biol. 2004 Dec;11(12):1607-17
references: 15610844
references: J Mol Biol. 2003 Feb 7;326(1):117-25
references: 12547195
references: Nature. 2002 Jun 20;417(6891):876-80
references: 12050675
references: Science. 1986 Jun 6;232(4755):1255-8
references: 3704650
references: J Biosci. 2002 Feb;27(1 Suppl 1):53-65
references: 11927777
references: Biochemistry. 2007 Jul 24;46(29):8498-516
references: 17602664
references: Adv Carbohydr Chem Biochem. 2006;60:251-302
references: 16750445
references: J Am Chem Soc. 2003 Apr 2;125(13):3733-44
references: 12656603
references: Nucleic Acids Res. 2007;35(2):477-85
references: 17169989
references: Anticancer Drug Des. 1987 Apr;1(4):323-35
references: 3450302
references: Acta Crystallogr D Biol Crystallogr. 2010 Mar;66(Pt 3):251-7
references: 20179336
references: Biochemistry. 1991 Apr 23;30(16):3812-5
references: 2018756
references: J Am Chem Soc. 2006 Dec 20;128(50):16092-103
references: 17165762
references: Curr Opin Chem Biol. 1999 Dec;3(6):688-93
references: 10600731
references: J Am Chem Soc. 2010 Oct 20;132(41):14521-9
references: 20812704
references: J Am Chem Soc. 2003 Aug 27;125(34):10148-9
references: 12926918
references: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1905-9
references: 11842222
references: J Am Chem Soc. 2005 Jan 19;127(2):742-50
references: 15643900
references: Proc Natl Acad Sci U S A. 1963 Aug;50:355-62
references: 14060656
references: J Am Chem Soc. 2002 Oct 30;124(43):12689-96
references: 12392416
references: J Am Chem Soc. 2009 Nov 11;131(44):16096-107
references: 19831353
references: Nat Rev Drug Discov. 2005 Apr;4(4):307-20
references: 15789122
references: Chem Rev. 1999 Sep 8;99(9):2467-98
references: 11749487
references: Nucleic Acids Res. 2007;35(2):363-70
references: 17175539
references: Curr Opin Chem Biol. 2004 Dec;8(6):580-91
references: 15556400
references: Nucleic Acids Res. 2000 May 15;28(10):2171-6
references: 10773088
references: Eur J Med Chem. 2008 Dec;43(12):2901-8
references: 18455271
references: J Mol Biol. 1985 Jun 25;183(4):553-63
references: 2991536
references: Med Res Rev. 2004 Jul;24(4):475-528
references: 15170593
references: EMBO J. 2009 Feb 18;28(4):383-93
references: 19153606
references: Proc Natl Acad Sci U S A. 1985 Mar;82(5):1376-80
references: 2983343
references: Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2422-6
references: 2006181
references: Nucleic Acids Res. 2000 Mar 1;28(5):1252-8
references: 10666470
references: Bioorg Med Chem Lett. 2008 Nov 15;18(22):5851-5
references: 18524590
references: EMBO J. 1990 Apr;9(4):1329-34
references: 2323343
references: Inorg Chem. 2007 Aug 6;46(16):6245-51
references: 17407284
references: ChemMedChem. 2007 Nov;2(11):1631-8
references: 17722211
references: Eur J Biochem. 1992 Feb 15;204(1):69-74
references: 1740157
references: J Am Chem Soc. 2007 Dec 26;129(51):16048-56
references: 18052170
references: Nat Chem Biol. 2005 Jun;1(1):39-43
references: 16407992
references: Biopolymers. 1997;44(3):201-15
references: 9591476
references: Angew Chem Int Ed Engl. 2001 Dec 17;40(24):4749-4751
references: 12404405
references: Biochemistry. 2004 Jan 27;43(3):641-50
references: 14730968
references: Curr Opin Chem Biol. 2008 Apr;12(2):197-206
references: 18155674
references: Biochim Biophys Acta. 1990 Nov 9;1036(2):121-7
references: 2223830
references: Nucleic Acids Res. 1988 Feb 11;16(3):1063-78
references: 2830590
references: J Am Chem Soc. 2009 Jun 24;131(24):8416-24
references: 19530727
references: J Biol Chem. 2002 Sep 20;277(38):35509-15
references: 12101184
references: J Mol Biol. 1989 Apr 20;206(4):693-705
references: 2738914
references: J Med Chem. 1997 Jul 4;40(14):2113-6
references: 9216827
references: Q Rev Biophys. 1989 May;22(2):93-138
references: 2675172
references: Med Chem. 2009 May;5(3):216-26
references: 19442211
references: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13175-9
references: 19666554
references: J Am Chem Soc. 2003 Oct 15;125(41):12398-9
references: 14531669
references: J Am Chem Soc. 2011 Jul 6;133(26):10171-83
references: 21627167
references: Gene. 2008 Jan 31;408(1-2):124-32
references: 18022767
references: J Mol Biol. 1961 Feb;3:18-30
references: 13761054
references: Biochemistry. 2005 Nov 15;44(45):14701-8
references: 16274217
references: J Phys Chem B. 2007 May 17;111(19):5047-52
references: 17455977
references: Nucleic Acids Res. 1992 May 25;20(10):2411-20
references: 1598199
references: Annu Rev Biophys Biomol Struct. 2005;34:415-40
references: 15869397
references: Biochemistry. 2007 Apr 17;46(15):4545-53
references: 17375936
references: J Am Chem Soc. 2004 Jan 21;126(2):448-9
references: 14719925
references: Annu Rev Biophys Biomol Struct. 1994;23:541-76
references: 7919793
references: Biochemistry. 1991 Mar 5;30(9):2483-94
references: 2001374
references: Biochemistry. 2009 Jun 30;48(25):5943-52
references: 19405506
references: Nucleic Acids Res. 2005 Jul 27;33(13):4106-16
references: 16049022
references: Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):442-8
references: 15805599
references: J Biomol Struct Dyn. 1989 Dec;7(3):477-91
references: 2627296
references: J Med Chem. 2009 Dec 10;52(23):7380-8
references: 19572551
references: Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1914-8
references: 1311854
references: Bioorg Med Chem Lett. 1999 Sep 6;9(17):2463-8
references: 10498189