Planejamento de novos candidatos a fármacos tuberculostáticos: modelagem molecular e QSAR
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Data
2013-01-08
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Universidade Federal de Goiás
Resumo
Tuberculosis (TB) is a chronic infectious and contagious disease with high epidemiological
rates. The rise of multi- and extensively drug-resistant strains as well as the side effects and
the long term treatment become urgent the development of novel therapy options. The
enzyme thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) is
essential to DNA synthesis and cell replication. Moreover, this enzyme has unique structural
characteristics among TMPKs family, emerging as a potential target to rational design of
novel anti-TB agents. The present work had as objective the application of Computer Aided
Drug-Design (CADD) strategies, using a set of 109 thymidine analogues inhibitors of
TMPKmt selected from the literature, aiming to elucidate the structural features relevant to
the biological activity of this set of compounds and generate models able to predict the
activity of untested compounds. Methodologies of 2D-QSAR (HQSAR), 3-D-QSAR
(CoMFA and CoMSIA), QM/MM docking and bioisosteric fragment replacement were
performed for proposing new TMPKmt inhibitors. The final models of HQSAR, CoMFA and
CoMSIA exhibit good internal and external consistency, presenting good correlation ability
and prediction of biological activity. The HQSAR contribution maps and the contour maps of
CoMFA and CoMSIA provided important information about structural features related to
affinity, such as the favorable presence of hydrophobic and less bulky substituents on thymine
ring and more bulky, electronegative, hydrophilic and hydrogen acceptors on sulfone of
naphtosultam ring. Gathering the information provided, it was planned nine new compounds
as potential TMPKmt inhibitors, which showed optimized affinity and physicochemical
properties.
Descrição
Palavras-chave
Tuberculose , Planejamento de fármacos , TMPK , HQSAR , CoMFA , CoMSIA , Docking , Tuberculosis , Drug design
Citação
BUENO, Renata Vieira. Planejamento de novos candidatos a fármacos tuberculostáticos: modelagem molecular e QSAR. 2013. 109 f. Dissertação (Mestrado em Enfermagem) - Universidade Federal de Goiás, Goiânia, 2013.