Performance of Dark Chemical Matter in High Throughput Screening

Muegge, Ingo; Mukherjee, Prasenjit

doi:10.1021/acs.jmedchem.6b01038

Cited by 13 publications

(11 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, MW does not properly distinguish between inactive and white molecules as shown in other datasets. For instance, promiscuity is enhanced by lower values of MW in a dataset from Pfizer ( Hopkins et al, 2006 ), but higher values in datasets from Novartis ( Azzaoui et al, 2007 ), Roche ( Peters et al, 2009 ) and Boehringer Ingelheim ( Muegge and Mukherjee, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

2017

View full text Add to dashboard Cite

Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015) have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels) shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process. Additionally, synergistic effects may be obtained by library design toward polypharmacology.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

2017

View full text Add to dashboard Cite

show abstract

“…However, designing libraries based on chemical diversity alone does not seem to yield sets of molecules with diverse biological activities or to improve their hit rates [17] . It is speculated that this is due to the fact that a large percentage of novel synthesized chemical matter does not possess relevant bioactivity [18–20] . Therefore, it is critical that new libraries be evaluated for biological activity as they are synthesized to characterize which features, if any, can be selected to create sets of molecules with high biological performance diversity.…”

Section: Introductionmentioning

confidence: 99%

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

et al. 2020

View full text Add to dashboard Cite

A systematic, diversity-oriented synthesis approach was employed to access a natural product-inspired flavonoid library with diverse chemical features, including chemical properties, scaffold, stereochemistry, and appendages. Using Cell Painting, the effects of these diversity elements were evaluated, and multiple chemical features that predict biological performance diversity were identified. Scaffold identity appears to be the dominant predictor of performance diversity, but stereochemis-try and appendages also contribute to a lesser degree. In addition, the diversity of chemical properties contributed to performance diversity, and the driving chemical property was dependent on the scaffold. These results highlight the importance of key chemical features that may inform the creation of small-molecule, performance-diverse libraries to improve the efficiency and success of high-throughput screening campaigns.

show abstract

“…The top-scoring compounds are then recommended for experimental testing. The resulting hit rates are far from 100%, but they tend to be better than those obtained from more costly high-throughput experimental screens ( Muegge and Mukherjee, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Webina: an open-source library and web app that runs AutoDock Vina entirely in the web browser

et al. 2020

View full text Add to dashboard Cite

Motivation Molecular docking is a computational technique for predicting how a small molecule might bind a macromolecular target. Among docking programs, AutoDock Vina is particularly popular. Like many docking programs, Vina requires users to download/install an executable file and to run that file from a command-line interface. Choosing proper configuration parameters and analyzing Vina output is also sometimes challenging. These issues are particularly problematic for students and novice researchers. Results We created Webina, a new version of Vina, to address these challenges. Webina runs Vina entirely in a web browser, so users need only visit a Webina-enabled webpage. The docking calculations take place on the user’s own computer rather than a remote server. Availability A working version of the open-source Webina app can be accessed free of charge from http://durrantlab.com/webina. Supplementary information Supplementary data are available at Bioinformatics online.

show abstract

Performance of Dark Chemical Matter in High Throughput Screening

Cited by 13 publications

References 24 publications

Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

Multiple Chemical Features Impact Biological Performance Diversity of a Highly Active Natural Product‐Inspired Library

Webina: an open-source library and web app that runs AutoDock Vina entirely in the web browser

Contact Info

Product

Resources

About