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Structure-Based Drug Design Targeting Infectious Disease: Overcoming Resistance and Extending the Antimicrobial Spectrum of Macrolide Antibioticsтезисы доклада
- Авторы: Bhattacharjee A., Kanyo Z., Wu Y., Tang Y., Martynow J., Collin F., Ippolito J., Skripkin E., Duffy E.
- Сборник: The 34th National Medicinal Chemistry Symposium
- Тезисы
- Год издания: 2014
- Место издания: Charleston, SC, USA
- Первая страница: 118
- Аннотация: The central theme of our research efforts is the rational design of novel drug molecules that target the 50S ribosomal subunit1, 2, 3 and that show activity against prevalent and emerging drug-resistant bacteria. These features distinguish our approach: (1) through crystallography, we have industrialized the process of obtaining atomic-level details of how established antibiotics bind to the 50S ribosomal subunit, thereby interfering with its function, and how ribosomal mutations or modifications affect this binding; (2) we have characterized these binding motifs in our archaebacterial system, Haloarcula marismortui; (3) we have a trainable and predictive computational suite of tools that allows us to build new molecules that both interact efficiently with functionally-relevant sites in the 50S ribosomal subunit and have optimal molecular properties4 that deliver a desired microbiological spectrum as well as a suitable ADME profile, and (4) we have embedded this technology in a drug discovery process that is complemented by efficient molecular synthesis and a screening strategy that is standard to the industry for assessing antibacterial drug candidates. Using this process, we have designed and developed several distinct classes of enhanced macrolide antibiotics that are robust to resistance, that are efficacious in animal models of infection and that challenge decades of medicinal chemistry assumptions regarding valid directions for optimization of this medically-valuable family. The structural analysis, chemical synthesis and molecular tuning for multiple target indications will be described in this poster. Melinta Therapeutics, Inc. 300 George Street, New Haven, CT 06511 USA
- Добавил в систему: Скрипкин Евгений Алексеевич