Structure-based drug design strategies in medicinal chemistry

A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of\ud leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD)\ud methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current\ud developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well\ud as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful\ud applications for the identification of novel active compounds.CNPqFAPES

Identification of Novel Compounds with Anti-Mycobacterial Activity Using in Silico Screening and Pharmacophore Modeling Targeting Mycobacterium Thymidine Monophosphate Kinase

The increasing prevalence of drug-resistant tuberculosis (TB), which is resistant to effective multiple antibiotic, remains a major public health menace. The Mycobacterium tuberculosis (M. tuberculosis) thymidine monophosphate kinase (mtTMPK), which is an essential enzyme for the maintenance of the thymidine triphosphate pools, is considered a potential enzymatic target for the development of effective antibiotics against TB. In this study, I attempted to identify novel compounds with anti-mycobacterial activity specifically targeting mtTMPK. I performed in silico structure-based drug screening (SBDS) with a large-scale virtual compound library (6,192,932 compounds) and phramacophore-based in silico screening with a compound library of 461,383 compounds. I then evaluated the inhibitory effects of candidate compounds on model mycobacteria strains. As a result, I found that compounds K10, KTP3, KTPS1, and KTPS2, completely inhibited the growth of Mycobacterium vanbaalenii (M. vanbaalenii) and/or Mycobacterium smegmatis (M. smegmatis). In addition, I experimentally demonstrated that two compounds (KTPS1 and KTPS2) directly inhibitedmtTMPK catalytic activity to some extent. Moreover, the most potent chemical compounds, KTPS1, did not exhibit any significant toxic effects on the growth of model intestinal bacteria (Escheichila coli: E. coli) and several mammalian cells. The structural and experimental information regarding these chemical compounds is likely useful for the development of novel antibiotics for the treatment of TB.九州工業大学博士学位論文 学位記番号:情工博甲第298号 学位授与年月日:平成27年3月25日1. Introduction|2. Results|3. Discussion|4. Conclusion|5. Materials and methods九州工業大学平成26年

CHARACTERIZATION OF BIOLOGICALLY AND THERAPEUTICALLY RELEVANT COMPOUNDS FROM STRUCTURE AND TARGET PERSPECTIVES

Ph.DDOCTOR OF PHILOSOPH