One cannot rule them all: Are bacterial toxins-antitoxins druggable?
Bottom Line: The result is a cessation of cell growth or even death.Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair.Possible ways of delivery and formulation of Tas are also discussed.
Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.Show MeSH
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Mentions: Alternatively to traditional high-throughput screening of libraries, fragment-based methods for drug discovery (Erlanson, McDowell and O’Brien 2004) has emerged as a stunning approach and mainstream for the discovery of new drugs within most pharmaceutical companies and many academic groups (Fig. 4). Comparison of putative candidates for novel drugs indicated that drugs derived from fragment-based screens could uncover novel compounds with more drug-like properties than those derived from more conventional drug discovery techniques. The search of these fragments is driven by the Rule of Three: molecular mass <300 Da, the number of hydrogen bond donors and acceptors each ≤3 and the clogP ≤3 (Congreve et al., 2003). The fragment-based lead discovery deals with low molecular mass and low affinity molecules, so that later on they can be optimized into drug leads (Park, Mann and Li 2013). This fragment-based approach has been very successful since it has allowed the marketing of a drug, vemurafenib (a drug for metastatic melanoma), in only six years (Baker 2013). In addition, several groups in the UK have joined to develop the 3D Fragment Consortium (http://www.3DFrag.org) devoted to the building of a shared library (500–3000 fragments) with enhanced three dimensionality of compounds that seem to be more advantageous than the traditional approach.
Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.