Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identifying lead hits in catalyst discovery by screening and deconvoluting complex mixtures of catalyst components.

ABSTRACT: A reaction-economic combinatorial strategy is described for lead hit identification in catalyst discovery efforts directed towards a specific transformation. Complex mixtures of rationally chosen precatalysts and ligands are screened against various reaction parameters to identify lead conditions in a small number of reactions. Iterative deconvolution of the resulting hits identifies which components contribute to the lead in situ generated catalyst. Application of this strategy rapidly uncovered a new mild in situ generated catalyst for the dehydrative Friedel-Crafts reaction as well as conditions for selective monoarylation in catalytic ortho-C-H arylation of unsubstituted N-(quinolin-8-yl)benzamide.

SUBMITTER: Wolf E

PROVIDER: S-EPMC5647744 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identifying lead hits in catalyst discovery by screening and deconvoluting complex mixtures of catalyst components.

Wolf Eléna E Richmond Edward E Moran Joseph J

Chemical science 20150216 4

A reaction-economic combinatorial strategy is described for lead hit identification in catalyst discovery efforts directed towards a specific transformation. Complex mixtures of rationally chosen precatalysts and ligands are screened against various reaction parameters to identify lead conditions in a small number of reactions. Iterative deconvolution of the resulting hits identifies which components contribute to the lead <i>in situ</i> generated catalyst. Application of this strategy rapidly u ...[more]

PMID: 29308159

Similar Datasets

Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures.

Project description:Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.

| S-EPMC9814918 | biostudies-literature

Lead Discovery Using Virtual Screening

Project description:The practice of virtual screening (VS) to identify chemical leads to known or novel targets is becoming a core function of the computational chemist within industry. By employing a range of techniques, when attempting to identify compounds with activity against a biological target, a small focused subset of a larger collection of compounds can be identified and tested, often with results much better than selecting a similar number of compounds at random. We will review the key methods available, their relative success, and provide practical insights into best practices and key gaps. We will also argue that the capability of VS methods has grown to a point where fuller integration with experimental methods, including HTS, could increase the effectiveness of both.

| S-EPMC7176223 | biostudies-literature

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.

Project description:Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization.

| S-EPMC5844225 | biostudies-literature

De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits.

Project description:Nonspecific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1 A and cyclorasin 9A5, exemplify false-positive molecules-in terms of both their binding affinities and cellular activities. Through multiple gold-standard biophysical techniques, we unambiguously show that both peptides lack specific binding to KRas and instead induce protein unfolding. Although these peptides inhibited cellular proliferation, the activities appeared to be off-target on the basis of a counterscreen with KRas-independent cell lines. We further demonstrate that their cellular activities are derived from membrane disruption. Accordingly, we propose that to de-risk false-positive molecules, orthogonal binding assays and cellular counterscreens are indispensable.

| S-EPMC7549268 | biostudies-literature

Identifying Mixtures of Mixtures Using Bayesian Estimation.

Project description:The use of a finite mixture of normal distributions in model-based clustering allows us to capture non-Gaussian data clusters. However, identifying the clusters from the normal components is challenging and in general either achieved by imposing constraints on the model or by using post-processing procedures. Within the Bayesian framework, we propose a different approach based on sparse finite mixtures to achieve identifiability. We specify a hierarchical prior, where the hyperparameters are carefully selected such that they are reflective of the cluster structure aimed at. In addition, this prior allows us to estimate the model using standard MCMC sampling methods. In combination with a post-processing approach which resolves the label switching issue and results in an identified model, our approach allows us to simultaneously (1) determine the number of clusters, (2) flexibly approximate the cluster distributions in a semiparametric way using finite mixtures of normals and (3) identify cluster-specific parameters and classify observations. The proposed approach is illustrated in two simulation studies and on benchmark datasets. Supplementary materials for this article are available online.

| S-EPMC5455957 | biostudies-literature

Towards identifying potent new hits for glioblastoma.

Project description:Glioblastoma is a devastating disease of the brain and is the most common malignant primary brain tumour in adults. The prognosis for patients is very poor with median time of survival after diagnosis measured in months, due in part to the tumours being highly aggressive and often resistant to chemotherapies. Alongside the ongoing research to identify key factors involved in tumour progression in glioblastoma, medicinal chemistry approaches must also be used in order to rapidly establish new and better treatments for brain tumour patients. Using a computational similarity search of the ZINC database, alongside traditional analogue design by medicinal chemistry intuition to improve the breadth of chemical space under consideration, six new hit compounds (14, 16, 18, 19, 20 and 22) were identified possessing low micromolar activity against both established cell lines (U87MG and U251MG) and patient-derived cell cultures (IN1472, IN1528 and IN1760). Each of these scaffolds provides a new platform for future development of a new therapy in this area, with particular promise shown against glioblastoma subtypes that are resistant to conventional chemotherapeutic agents.

| S-EPMC6253844 | biostudies-literature

Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.

Project description:Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.

| S-EPMC9749961 | biostudies-literature

Identifying effective intervention components for smoking cessation: a factorial screening experiment.

Project description:To identify promising intervention components intended to help smokers to attain and maintain abstinence in their quit smoking attempts.A fully crossed, six-factor randomized fractional factorial experiment.Eleven primary care clinics in southern Wisconsin, USA.A total of 637 adult smokers (55% women, 88% white) motivated to quit smoking who visited primary care clinics.Six intervention components designed to prepare smokers to quit, and achieve and maintain abstinence (i.e. for the preparation, cessation and maintenance phases of smoking treatment): (1) preparation nicotine patch versus none; (2) preparation nicotine gum versus none; (3) preparation counseling versus none; (4) intensive cessation in-person counseling versus minimal; (5) intensive cessation telephone counseling versus minimal; and (6) 16 versus 8?weeks of combination nicotine replacement therapy (nicotine patch ?+? nicotine gum).Seven-day self-reported point-prevalence abstinence at 16?weeks.Preparation counseling significantly improved week 16 abstinence rates (P = .04), while both forms of preparation nicotine replacement therapy interacted synergistically with intensive cessation in-person counseling (P?<?0.05). Conversely, intensive cessation phone counseling and intensive cessation in-person counseling interacted antagonistically (P?<?0.05)-these components produced higher abstinence rates by themselves than in combination.Preparation counseling and the combination of intensive cessation in-person counseling with preparation nicotine gum or patch are promising intervention components for smoking and should be evaluated as an integrated treatment package.

| S-EPMC4699315 | biostudies-literature

Identifying Major Drivers of Antioxidant Activities in Complex Polyphenol Mixtures from Grape Canes.

Project description:Grape canes represent a valuable source of numerous polyphenols with antioxidant properties, whose compositions vary depending on the genotype and environmental factors. Antioxidant activities of pure molecules are often reported without considering possible interactions that may occur in complex polyphenol mixture. Using UPLC-MS-based metabolomics and unsupervised classification, we explored the polyphenol variations in grape cane extracts from a collection of European varieties. Antioxidant activities were assessed using ORAC, ABTS, DPPH, FRAP, CUPRAC and chelation assays. Pairwise correlations between polyphenols and antioxidant capacities were performed to identify molecules that contributed more to the antioxidant capacities within a complex mixture of polyphenols.

| S-EPMC9268674 | biostudies-literature

An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery.

Project description:Fragment-based lead discovery has proved to be an effective alternative to high-throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we describe an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against MEK1 kinase. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating the potential of MST to execute and maximize the efficacy of fragment screening campaigns.

| S-EPMC4800460 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data