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One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan WT, Balsa D, Espinosa M - FEMS Microbiol. Rev. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.

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Related in: MedlinePlus

Combination of combinatorial chemistry with high throughput has contributed to the development of large screening libraries of compounds. However, the largest imaginable collection of compounds falls short of potential chemical diversity space. As molecular size decreases, the number of possible molecules decreases exponentially. Thus, at least from a theoretical point of view, it would result easier to screen large collections of very small molecules (‘fragments’) and, later on proceed to expand, merge or link them. Fragment screening is an excellent method for the identification and validation of lead compounds that can later on be tested for development of therapeutic agents. Fragments are small (MW <300 Da) and can provide the sampling of chemical space more effectively than other screening methods. Highly ligand efficient hits have been identified for several soluble proteins and for i-PPIs purposes. Determination of the 3D structure of the target proteins in conjunction to compounds with a greater degree of 3D shape is a good method to increase the diversity of libraries. Finally, through different rounds of chemical modifications and/or combination with other molecules, fragments with increased affinity for the target protein can be developed.
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fig4: Combination of combinatorial chemistry with high throughput has contributed to the development of large screening libraries of compounds. However, the largest imaginable collection of compounds falls short of potential chemical diversity space. As molecular size decreases, the number of possible molecules decreases exponentially. Thus, at least from a theoretical point of view, it would result easier to screen large collections of very small molecules (‘fragments’) and, later on proceed to expand, merge or link them. Fragment screening is an excellent method for the identification and validation of lead compounds that can later on be tested for development of therapeutic agents. Fragments are small (MW <300 Da) and can provide the sampling of chemical space more effectively than other screening methods. Highly ligand efficient hits have been identified for several soluble proteins and for i-PPIs purposes. Determination of the 3D structure of the target proteins in conjunction to compounds with a greater degree of 3D shape is a good method to increase the diversity of libraries. Finally, through different rounds of chemical modifications and/or combination with other molecules, fragments with increased affinity for the target protein can be developed.

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.


One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan WT, Balsa D, Espinosa M - FEMS Microbiol. Rev. (2015)

Combination of combinatorial chemistry with high throughput has contributed to the development of large screening libraries of compounds. However, the largest imaginable collection of compounds falls short of potential chemical diversity space. As molecular size decreases, the number of possible molecules decreases exponentially. Thus, at least from a theoretical point of view, it would result easier to screen large collections of very small molecules (‘fragments’) and, later on proceed to expand, merge or link them. Fragment screening is an excellent method for the identification and validation of lead compounds that can later on be tested for development of therapeutic agents. Fragments are small (MW <300 Da) and can provide the sampling of chemical space more effectively than other screening methods. Highly ligand efficient hits have been identified for several soluble proteins and for i-PPIs purposes. Determination of the 3D structure of the target proteins in conjunction to compounds with a greater degree of 3D shape is a good method to increase the diversity of libraries. Finally, through different rounds of chemical modifications and/or combination with other molecules, fragments with increased affinity for the target protein can be developed.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487406&req=5

fig4: Combination of combinatorial chemistry with high throughput has contributed to the development of large screening libraries of compounds. However, the largest imaginable collection of compounds falls short of potential chemical diversity space. As molecular size decreases, the number of possible molecules decreases exponentially. Thus, at least from a theoretical point of view, it would result easier to screen large collections of very small molecules (‘fragments’) and, later on proceed to expand, merge or link them. Fragment screening is an excellent method for the identification and validation of lead compounds that can later on be tested for development of therapeutic agents. Fragments are small (MW <300 Da) and can provide the sampling of chemical space more effectively than other screening methods. Highly ligand efficient hits have been identified for several soluble proteins and for i-PPIs purposes. Determination of the 3D structure of the target proteins in conjunction to compounds with a greater degree of 3D shape is a good method to increase the diversity of libraries. Finally, through different rounds of chemical modifications and/or combination with other molecules, fragments with increased affinity for the target protein can be developed.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.

Show MeSH
Related in: MedlinePlus