De Novo Fragment Design for Drug Discovery and Chemical Biology

Rodrigues, Tiago; Reker, Daniel; Welin, M.; Caldera, Michael; Brunner, C; Gabernet, Gisela; Schneider, Petra; Walse, Björn

doi:10.1002/anie.201508055

Cited by 32 publications

(16 citation statements)

References 40 publications

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“…DAPK3 is as erine/threonine kinase with potential as atarget for innovative therapeutics to treat hypertension and smooth muscle disorders.Inanother application of the DOGS program, [48] the known ROCK inhibitor fasudil (which has an IC 50 for DAPK3 of 1.2 mm ;F igure 11) served as the starting point for ligand-based de novo design. Thep rogram generated 521 designs of which 357 fulfilled fragment-like criteria.…”

Section: Af Ragment-like Inhibitor Of Dapk3mentioning

confidence: 99%

Automated De Novo Drug Design: Are We Nearly There Yet?

2019

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Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

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Section: Af Ragment-like Inhibitor Of Dapk3mentioning

confidence: 99%

Automated De Novo Drug Design: Are We Nearly There Yet?

2019

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“…Yet, within their respective application fields, specific rules have been used to discover novel molecules and reaction pathways. Taking experimentally validated examples, the rules associated with the ligand-based de novo design software DOGS (inSili.com LLC) [ 4 ] have enabled the production of new chemical entities inhibitors of DAPK3 (death-associated protein kinase 3) [ 20 ], metabolic rules for promiscuous enzymes have allowed the discovery of novel metabolites in E. coli [ 21 ] and have also been used to engineer metabolic pathways producing 1,4-butanediol [ 9 ] and flavonoids [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular structures enumeration and virtual screening in the chemical space with RetroPath2.0

Koch¹,

Duigou²,

Carbonell³

et al. 2017

J Cheminform

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Background: Network generation tools coupled with chemical reaction rules have been mainly developed for synthesis planning and more recently for metabolic engineering. Using the same core algorithm, these tools apply a set of rules to a source set of compounds, stopping when a sink set of compounds has been produced. When using the appropriate sink, source and rules, this core algorithm can be used for a variety of applications beyond those it has been developed for. Results:Here, we showcase the use of the open source workflow RetroPath2.0. First, we mathematically prove that we can generate all structural isomers of a molecule using a reduced set of reaction rules. We then use this enumeration strategy to screen the chemical space around a set of monomers and predict their glass transition temperatures, as well as around aminoglycosides to search structures maximizing antibacterial activity. We also perform a screening around aminoglycosides with enzymatic reaction rules to ensure biosynthetic accessibility. We finally use our workflow on an E. coli model to complete E. coli metabolome, with novel molecules generated using promiscuous enzymatic reaction rules. These novel molecules are searched on the MS spectra of an E. coli cell lysate interfacing our workflow with OpenMS through the KNIME Analytics Platform. Conclusion:We provide an easy to use and modify, modular, and open-source workflow. We demonstrate its versatility through a variety of use cases including molecular structure enumeration, virtual screening in the chemical space, and metabolome completion. Because it is open source and freely available on MyExperiment.org, workflow community contributions should likely expand further the features of the tool, even beyond the use cases presented in the paper.

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“…DAPK3 is a serine/threonine kinase with potential as a target for innovative therapeutics to treat hypertension and smooth muscle disorders. In another application of the DOGS program, the known ROCK inhibitor fasudil (which has an IC 50 for DAPK3 of 1.2 μ m ; Figure ) served as the starting point for ligand‐based de novo design. The program generated 521 designs of which 357 fulfilled fragment‐like criteria.…”

Section: A Fragment‐like Inhibitor Of Dapk3mentioning

confidence: 99%