Chemical space as a source for new drugs

Reymond, Jean‐Louis; Deursen, Ruud van; Blum, Lorenz C.; Ruddigkeit, Lars

doi:10.1039/c0md00020e

Cited by 287 publications

(225 citation statements)

References 116 publications

(122 reference statements)

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“…Together, bioactivity of 86% (248 of 281) of the test compounds against MzR G. lamblia was correctly predicted, indicating the excellent utility of the predictive model. The findings experimentally validate prior contentions that structural analysis by chemical descriptors can be exploited to define chemical spaces with promising structure−activity relationships (19,20). As for the training compounds, the vast majority of test compounds (260/279, 93%) had no measurable cytotoxicity in human HeLa cells (SI Appendix, Table S8).…”

Section: Distinct and Predictive Bioactivity Landscapes Of 5-ni Composupporting

confidence: 67%

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.infectious diseases | antibiotics | medicinal chemistry

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Section: Distinct and Predictive Bioactivity Landscapes Of 5-ni Composupporting

confidence: 67%

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Firstly, the available chemical space is very large (Reymond et al 2010;Reymond 2015) and the proportion taken up by the existing set of preclinical or clinical compounds is very small. Secondly even if one is able to match a drug with a target implicated in a given disease, considerable resources and time will still be required to move the drug into the new indication, depending on the level of development it has reached.…”

Section: Discussionmentioning

confidence: 99%

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia

et al. 2016

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Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbor information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9,389 gene sets (2,

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“…This database was an extension of a previous version GDB-11 containing 26.4 million virtual molecules up to 11 non-hydrogen atoms of C, N, O, F [12,13], which was shown to provide a useful starting point for designing bioactive synthetic ligands [14][15][16][17]. GDB-13 exceeds the number of known molecules of similar size by several orders of magnitude and represents a vast and mostly unexploited reservoir for innovation [18].…”

Section: Introductionmentioning

confidence: 99%

Visualisation and subsets of the chemical universe database GDB-13 for virtual screening

Blum

Deursen

Reymond

2011

J Comput Aided Mol Des

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The chemical universe database GDB-13, which enumerates 977 million organic molecules up to 13 atoms of C, N, O, S and Cl following simple chemical stability and synthetic feasibility rules, represents a vast reservoir for new fragments. GDB-13 was classified using the MQN-system discussed in the preceding paper for the analysis of PubChem fragments. Two hundred and fiftyfive subsets of GDB-13 were generated by the combinatorial use of eight restrictive criteria, including fragmentlike (''rule of three'') and scaffold-like (no acyclic carbon atoms) filters. Virtual screening for analogs of 15 commercial drugs of 13 non-hydrogen atoms or less shows that retrieving MQN-neighbors of a query molecule from GDB-13 or its subsets provides on average a 38-fold enrichment in structural analogs (Daylight-type substructure fingerprint Tanimoto T SF [ 0.7), and a 75-fold enrichment in shapesimilar analogs (ROCS TanimotoCombo score [ 1.4). An MQN-searchable version of GDB-13 is provided at www.gdb.unibe.ch.

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Chemical space as a source for new drugs

Cited by 287 publications

References 116 publications

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia

Visualisation and subsets of the chemical universe database GDB-13 for virtual screening

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