Planejamento de novos candidatos a fármacos tuberculostáticos: modelagem molecular e QSAR

• Autor(a) principal: Bueno, Renata Vieira
• Data de Publicação: 2013
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/001300000d3qf
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/3324
• topic: Tuberculose; Planejamento de fármacos; TMPK; HQSAR; CoMFA; CoMSIA; Docking; Tuberculosis; Drug design; FARMACIA::FARMACOTECNIA

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.