In silico structural characterization of protein targets for drug development against Trypanosoma cruzi.
Trypanosoma cruzi is the protozoan pathogen responsible for Chagas disease, which is a major public health problem in tropical and subtropical regions of developing countries and particularly in Brazil. Despite many studies, there is no efficient treatment against Chagas disease, and the search for new therapeutic targets specific to T. cruzi is critical for drug development. Here, we have revisited 41 protein sequences proposed by the analogous enzyme pipeline, and found that it is possible to provide structures for T. cruzi sequences with clear homologs or analogs in H. sapiens and likely associated with trypanothione reductase, cysteine synthase, and ATPase functions, and structures for sequences specific to T. cruzi and absent in H. sapiens associated with 2,4-dienoyl-CoA reductase, and leishmanolysin activities. The implications of our structures refined by atomistic molecular dynamics (monomer or dimer states) in their in vitro environments (aqueous solution or membrane bilayers) are discussed for drug development and suggest that all protein targets, except cysteine synthase, merit further investigation.
Molécules Thérapeutiques in silico, Université Paris Diderot, INSERM UMR-S 973, Sorbonne Paris Cité, 75013, Paris, France.|Laboratoire de Biochimie Théorique, CNRS UPR 9080, Institut de Biologie Physico - Chimique, Université Paris Diderot, Sorbonne Paris Cité, 75005, Paris, France.
Carlyle Ribeiro
CR
Lima
Laboratório de Modelagem de Sistemas Biológicos, National Institute for Science and Technology on Innovation in Neglected Diseases (INCT-IDN), Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.
Nicolas
N
Carels
Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz (IOC), FIOCRUZ, Rio de Janeiro, Brazil.
Ana Carolina Ramos
AC
Guimaraes
Molécules Thérapeutiques in silico, Université Paris Diderot, INSERM UMR-S 973, Sorbonne Paris Cité, 75013, Paris, France. pierre.tuffery@univ-paris-diderot.fr.
Pierre
P
Tufféry
Laboratoire de Biochimie Théorique, CNRS UPR 9080, Institut de Biologie Physico - Chimique, Université Paris Diderot, Sorbonne Paris Cité, 75005, Paris, France. philippe.derreumaux@ibpc.fr.
Philippe
P
Derreumaux
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D014355:Chagas Disease / Q000188:drug therapy / Q000378:metabolism; D003198:Computer Simulation; D003547:Cysteine Synthase / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism*
D015800:Protozoan Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C100153:2,4-dienoyl-CoA reductase; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D003547:Cysteine Synthase; D000251:Adenosine Triphosphatases
Drugs; Molecular dynamics; Protein targets; Structures; T. Cruzi
J Med Chem. 2011 Oct 13;54(19):6514-30
21851087
J Chem Phys. 2015 Jul 14;143(2):021101
26178083
J Phys Chem B. 2014 Jun 5;118(22):5807-16
24814976
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
10592173
Parasit Vectors. 2014 Apr 24;7:197
24761813
PLoS One. 2010 Apr 01;5(4):e9931
20368981
Expert Opin Drug Discov. 2016;11(5):447-55
26967915
Nucleic Acids Res. 2012 Jan;40(Database issue):D742-53
22102576
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W610-4
15215461
J Chem Theory Comput. 2014 Oct 14;10(10):4745-58
26588162
Bioinformatics. 2013 Apr 1;29(7):845-54
23407358
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W423-6
18477636
Science. 2011 Oct 28;334(6055):517-20
22034434
J Phys Chem B. 2015 Jun 11;119(23):6941-51
25985144
Mem Inst Oswaldo Cruz. 2015 Jun;110(4):566-8
26061148
Proteins. 2014 Feb;82 Suppl 2:14-25
24123179
Curr Top Med Chem. 2016;16(9):948-59
26303427
Bioinformatics. 2009 Nov 15;25(22):3005-11
19689959
J Mol Biol. 1982 May 5;157(1):105-32
7108955
BMC Genomics. 2010 Oct 29;11:610
21034488
Bioinformatics. 2013 Aug 15;29(16):2056-8
23772049
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W460-4
17567614
BMC Bioinformatics. 2008 Dec 17;9:544
19091081
J Phys Chem B. 2012 Jul 26;116(29):8412-22
22283547
Biochim Biophys Acta. 2009 Apr;1787(4):207-20
19388138
Biochem J. 2002 Nov 1;367(Pt 3):761-9
12137567
BMC Bioinformatics. 2013 Mar 27;14:112
23530693
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W665-7
15215472
Proteins. 2007 Mar 1;66(4):778-95
17186527
J Chem Phys. 2007 Jan 7;126(1):014101
17212484
Biochem J. 2013 Jun 15;452(3):423-32
23535070
J Comput Chem. 2004 Oct;25(13):1605-12
15264254
PLoS Negl Trop Dis. 2014 Feb 13;8(2):e2689
24551254
Science. 2005 Jul 15;309(5733):409-15
16020725
Biophys J. 2011 May 4;100(9):L47-9
21539772
BMC Bioinformatics. 2014;15 Suppl 8:S3
25080939
J Chem Inf Model. 2014 Feb 24;54(2):573-81
24460123
Nat Protoc. 2008;3(2):153-62
18274516
Vet Res. 2009 Mar-Apr;40(2):26
19250627
Biophys J. 1998 Jan;74(1):72-81
9449311
Genet Mol Res. 2008 Sep 23;7(3):872-82
18949706
Mol Microbiol. 2000 Feb;35(3):542-52
10672177
J Med Chem. 2005 Jul 28;48(15):4793-802
16033259
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1833-8
21239683
Nucleic Acids Res. 2014 Jan;42(Database issue):D222-30
24288371
Eur J Med Chem. 2016 Jan 1;107:109-18
26562546
Bioinformatics. 2015 Dec 1;31(23):3850-2
26231431
J Biol Chem. 2003 Sep 26;278(39):37553-60
12840019
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5022-7
18367671
BMC Bioinformatics. 2014 Dec 30;15:427
25547242
Arch Biochem Biophys. 2009 Jan 1;481(1):65-71
18983813
J Mol Graph Model. 2014 Mar;48:47-59
24370672
Mem Inst Oswaldo Cruz. 2009 Dec;104(8):1100-10
20140370
Biol Chem. 2003 Apr;384(4):539-49
12751784
Nucleic Acids Res. 2015 Jan;43(Database issue):D345-56
25428375
J R Soc Interface. 2012 Jan 7;9(66):20-33
21993006
Genome Res. 1998 Aug;8(8):779-90
9724324
Bioinformatics. 2005 Apr 1;21(7):951-60
15531603
Expert Rev Anti Infect Ther. 2009 Mar;7(2):157-63
19254164
Structure. 1998 Aug 15;6(8):1035-46
9739094
Antimicrob Agents Chemother. 2007 May;51(5):1852-4
17339374
J Biol Chem. 2005 Jan 28;280(4):3068-77
15531764
Methods Enzymol. 2011;487:545-74
21187238
Proteins. 2014 Feb;82 Suppl 2:26-42
24318984
Nature. 2007 Dec 13;450(7172):1111-4
18075595
Nucleic Acids Res. 2012 Jan;40(Database issue):D1118-27
22116064
PLoS Negl Trop Dis. 2016 Feb 25;10(2):e0004343
26913759
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W244-8
15980461
PLoS Negl Trop Dis. 2015 Jun 04;9(6):e0003773
26042772
Methods Mol Biol. 2014;1137:83-103
24573476
Bioinformatics. 2007 Nov 1;23(21):2947-8
17846036
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Mol Biol Int. 2011;2011:306928
22091400
J Proteome Res. 2014 Aug 1;13(8):3530-41
24978697
Eur Biophys J. 2014 Sep;43(8-9):361-6
24986473