Desenvolvimento de modelos de QSAR e planejamento de novos inibidores da enzima dUTPase de Plasmodium falciparum
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Data
2015-03-03
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Universidade Federal de Goiás
Resumo
Malaria is a serious endemic disease caused by parasites of the genus Plasmodium, which
affects much of the population, especially in tropical and subtropical areas. Currently, drug
therapy makes use of artemisinin or its derivatives associated with a second anti-malarial drug.
The shortage of new treatments as well as the spread of parasite resistance to drugs currently
available, makes urgent the search and discovery of new targets and new antimalarial drugs.
The enzyme deoxyuridine triphosphatase (dUTPase) of Plasmodium falciparum plays an
important role in maintaining balance between 2'-deoxyuridine 5'-triphosphate (dUTP) and 2'-
deoxitimina 5'-triphosphate (dTTP) in order to avoid the erroneous incorporation uracil on the
DNA tape. Thus, the enzyme dUTPase is a potential target for the development of new drugs,
and has been validated for the organisms Escherichia coli, Saccharomyces cerevisiae and
Mycobacterium smegmatis. This study aimed to carry out quantitative studies of the relationship
between structure and activity (QSAR) to a series of β-branched nucleoside inhibitors
PfdUTPase, in order to generate robust and predictive models to predict compounds activity
untested and that may help to elucidate the important structural requirements for the affinity of
this class of compounds. For this, there was the hologram QSAR analysis (HQSAR),
comparative molecular field analysis (CoMFA) and comparative molecular similarity index
analysis (CoMSIA). For studies of CoMFA and CoMSIA were tested two methods of
calculation of partial charges, the empirical method Gasteiger-Huckel and the semi-empirical
method AM1-BCC. Were also tested three structural alignment strategies based on the binder:
maximum common substructure, based on the overlap of molecular volumes, and on the basis
of morphological similarities; and a strategy based on the 3D coordinates of the enzymeinhibitor
complex (molecular docking). The QSAR models generated showed good robustness
and external predictability, showing good power correlation and prediction of affinity. The
HQSAR contribution maps and contour maps of the CoMFA and CoMSIA indicated the
importance of certain groups for affinity, such as the importance of the presence of at least two
of trityl rings that contribute both sterically as hydrophobically to interact with the hydrophobic
site of the parasite enzyme, non-existent in the human enzyme. The drug design based on
information obtained from 2D and 3D QSAR, generated 121 molecules grouped into 18
clusters. Two hits with approximate power to one of the most active compounds of the series
stood out by presenting appropriate physicochemical properties.
Descrição
Palavras-chave
Malária , Plasmodium falciparum , Planejamento de fármacos , dUTPase , HQSAR , CoMFA , CoMSIA , Malaria , Plasmodium falciparum , Drug design , dUTPase , HQSAR , CoMFA , CoMSIA
Citação
NASCIMENTO, M. N. Desenvolvimento de modelos de QSAR e planejamento de novos inibidores da enzima dUTPase de Plasmodium falciparum. 2015. 108 f. Dissertação (Mestrado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2015.