A molecular modeling and QSAR study of suppressors of the growth of Trypanosoma cruzi epimastigotes.

In this work, we have used molecular modeling and QSAR tools to study 18 dithiocarbamate suppressors of the growth of Trypanosoma cruzi epimastigotes, which have been reported in the literature as superoxide dismutase (SOD) inhibitors. The principal component analysis (PCA) showed that the descriptors superficial area, heat of formation, logarithm of the partition coefficient, charge of the nitrogen atom from the dithiocarbamate group and Charges of the two carbon atoms adjacent to that nitrogen are responsible for the classification between the higher and lower trypanomicid activity. Using multiple linear regression (MLR) and docking methods it was possible to identify the probable bioactive isomers that suppress of the growth of T. cruzi epimastigotes. Our best partial least square (PLS) model obtained with these six descriptors yields a good correlation between experimental and predicted biological activities and compares two different SODs as possible target for interaction with the dithiocarbamates.

[1]  M. Simonyi.  The concept of chiral conformers and its significance in molecular pharmacology , 1997 .

[2]  W. Stallings,et al.  Manganese superoxide dismutase from Thermus thermophilus. A structural model refined at 1.8 A resolution. , 1991, Journal of molecular biology.

[3]  J. Molenda,et al.  Chelating agent inhibition of Trypanosoma cruzi epimastigotes in vitro. , 1995, Journal of Inorganic Biochemistry.

[4]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[5]  A. Frasch,et al.  SAPA/trans‐sialidase and cruzipain: two antigens from Trypanosoma cruzi contain immunodominant but enzymatically inactive domains , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  S. Wilkinson,et al.  Cloning of an Fe-superoxide dismutase gene homologue from Trypanosoma cruzi. , 1996, Molecular and biochemical parasitology.

[7]  A. Katzin,et al.  Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi. , 1981, Molecular and biochemical parasitology.

[8]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[9]  V. Marder,et al.  NF-kappa B-dependent inhibition of apoptosis is essential for host cellsurvival during Rickettsia rickettsii infection. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G Vriend,et al.  Refined 1.83 A structure of trypanosomal triosephosphate isomerase crystallized in the presence of 2.4 M-ammonium sulphate. A comparison with the structure of the trypanosomal triosephosphate isomerase-glycerol-3-phosphate complex. , 1991, Journal of molecular biology.

[11]  James J. P. Stewart,et al.  MOPAC: A semiempirical molecular orbital program , 1990, J. Comput. Aided Mol. Des..

[12]  R. Ribeiro‐dos‐Santos,et al.  The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet. , 2001, Anais da Academia Brasileira de Ciencias.

[13]  A. Fairlamb,et al.  Metabolism and functions of trypanothione in the Kinetoplastida. , 1992, Annual review of microbiology.

[14]  J. Sussman,et al.  Characterization of crystals of genetically engineered human manganese superoxide dismutase. , 1989, Journal of molecular biology.

[15]  Han van de Waterbeemd,et al.  Chemometric methods in molecular design , 1995 .

[16]  Paola Gramatica,et al.  SD-modelling and Prediction by WHIM Descriptors. Part 5. Theory Development and Chemical Meaning of WHIM Descriptors , 1997 .

[17]  G Vriend,et al.  WHAT IF: a molecular modeling and drug design program. , 1990, Journal of molecular graphics.

[18]  W. Stallings,et al.  Iron superoxide dismutase. Nucleotide sequence of the gene from Escherichia coli K12 and correlations with crystal structures. , 1988, The Journal of biological chemistry.

[19]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[20]  '. FREDM.D.VELLIEUXa,et al.  Structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma brucei determined from Laue data. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Marco Di Benedetto,et al.  Solution structure of reduced monomeric Q133M2 copper, zinc superoxide dismutase (SOD). Why is SOD a dimeric enzyme?. , 1998, Biochemistry.

[22]  A. Leo.  CALCULATING LOG POCT FROM STRUCTURES , 1993 .

[23]  M. Sternberg,et al.  A strategy for the rapid multiple alignment of protein sequences. Confidence levels from tertiary structure comparisons. , 1987, Journal of molecular biology.

[24]  R J Fletterick,et al.  The crystal structure of cruzain: a therapeutic target for Chagas' disease. , 1995, Journal of molecular biology.

[25]  B. Honig,et al.  A rapid finite difference algorithm, utilizing successive over‐relaxation to solve the Poisson–Boltzmann equation , 1991 .

[26]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[27]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[28]  J. Cazzulo.  Aerobic fermentation of glucose by trypanosomatids , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  Barry L. Stoddard,et al.  The 2.1-A resolution structure of iron superoxide dismutase from Pseudomonas ovalis. , 1990, Biochemistry.

[30]  E. Dias,et al.  Clínica e terapêutica da doença de Chagas , 1948 .

[31]  L. Gedamu,et al.  Cloning, characterization and overexpression of two iron superoxide dismutase cDNAs from Leishmania chagasi: role in pathogenesis. , 1997, Molecular and biochemical parasitology.

[32]  F. Javier Luque,et al.  Ligand-induced changes in the binding sites of proteins , 2002, Bioinform..

[33]  D. Eisenberg,et al.  Assessment of protein models with three-dimensional profiles , 1992, Nature.

[34]  J. Eaton,et al.  Hemolytic and microbicidal actions of diethyldithiocarbamic acid. , 1991, Biochemical pharmacology.

[35]  Bradley E. Bernstein,et al.  Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation , 1997, Nature.

[36]  Daniel J. Rigden,et al.  Plant-like traits associated with metabolism of Trypanosoma parasites , 2003, Proceedings of the National Academy of Sciences of the United States of America.