skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


  • NSF Public Access
  • Search Results
  • Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides
Title: Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides
Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on-and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.  more » « less
Award ID(s):
1900366
PAR ID:
10494569
Author(s) / Creator(s):
; ; ; ; ; ;
Publisher / Repository:
American Chemical Society
Date Published:
Journal Name:
Journal of the American Chemical Society
ISSN:
0002-7863
Subject(s) / Keyword(s):
modeling ligand design nickel cross-electrophile coupling
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; (, Chemical reviews)
    Sharon Hammes-Schiffer, Editor-In-Chief Ruma Banerjee (Ed.)
    Reaction discovery and catalyst screening lie at the heart of synthetic organic chemistry. And while there are efforts at de novo catalyst design using computation/artificial intelligence; at its core, synthetic chemistry is an experimental science. This review overviews biomacromolecule-assisted screening methods and the follow-on elaboration of chemistry so discovered. All three types of biomacromolecules discussed–enzymes, antibodies, and nucleic acids–have been used as ‘sensors’ to provide a readout on product chirality exploiting their native chirality. Enzymatic sensing methods yield both UV-spectrophotometric and visible, colorimetric readouts. Antibody sensors provide direct fluorescent readout upon analyte binding in some cases, or provide for cat-ELISA (Enzyme-Linked ImmunoSorbent Assay)-type readouts. DNA biomacromolecule-assisted screening allows for templation to facilitate reaction discovery, driving bimolecular reactions into a pseudo-unimolecular format. Also, the ability to use DNA-encoded libraries permits the barcoding of reactants. All three types of biomacromolecule-based screens afford high sensitivity and selectivity. Among the chemical transformations discovered by enzymatic screening methods are the first Ni(0)-mediated asymmetric allylic amination, and a new thiocyanopalladation/carbocyclization transformation in which both C-SCN and C-C bonds are fashioned sequentially. Cat-ELISA screening has identified new classes of sydnone-alkyne cycloadditions and DNA-encoded screening has been exploited to uncover interesting oxidative Pd-mediated amido-alkyne/alkene coupling reactions. 
    more » « less
  2. ; ; ; ; (, Molecules)
    null (Ed.)
    As fragment-based drug discovery has become mainstream, there has been an increase in various screening methodologies. Protein-observed 19F (PrOF) NMR and 1H CPMG NMR are two fragment screening assays that have complementary advantages. Here, we sought to combine these two NMR-based assays into a new screening workflow. This combination of protein- and ligand-observed experiments allows for a time- and resource-efficient multiplexed screen of mixtures of fragments and proteins. PrOF NMR is first used to screen mixtures against two proteins. Hit mixtures for each protein are identified then deconvoluted using 1H CPMG NMR. We demonstrate the benefit of this fragment screening method by conducting the first reported fragment screens against the bromodomains of BPTF and Plasmodium falciparum (Pf) GCN5 using 467 3D-enriched fragments. The hit rates were 6%, 5% and 4% for fragments binding BPTF, PfGCN5, and fragments binding both proteins, respectively. Select hits were characterized, revealing a broad range of affinities from low µM to mM dissociation constants. Follow-up experiments supported a low-affinity second binding site on PfGCN5. This approach can be used to bias fragment screens towards more selective hits at the onset of inhibitor development in a resource- and time-efficient manner. 
    more » « less
  3. ; ; ; ; ; ; ; ; ; ; et al (, Nature Communications)
    Abstract Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel NaV1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to NaV1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery. 
    more » « less
  4. ; ; (, Journal of Industrial Microbiology and Biotechnology)
    Abstract  The multifaceted nature of CRISPR screens has propelled advancements in the field of functional genomics. Pooled CRISPR screens involve creating programmed genetic perturbations across multiple genomic sites in a pool of host cells subjected to a challenge, empowering researchers to identify genetic causes of desirable phenotypes. These genome-wide screens have been widely used in mammalian cells to discover biological mechanisms of diseases and drive the development of targeted drugs and therapeutics. Their use in non-model organisms, especially in microbes to improve bioprocessing-relevant phenotypes, has been limited. Further compounding this issue is the lack of bioinformatic algorithms for analyzing microbial screening data with high accuracy. Here, we describe the general approach and underlying principles for conducting pooled CRISPR knockout screens in non-conventional yeasts and performing downstream analysis of the screening data, while also reviewing state-of-the-art algorithms for identification of CRISPR screening outcomes. Application of pooled CRISPR screens to non-model yeasts holds considerable potential to uncover novel metabolic engineering targets and improve industrial bioproduction. One-Sentence SummaryThis mini-review describes experimental and computational approaches for functional genomic screening using CRISPR technologies in non-conventional microbes. 
    more » « less
  5. ; (, Israel Journal of Chemistry)
    Abstract In less than a decade, CRISPR screening has revolutionized forward genetics and cell and molecular biology. Advances in screening technologies, including sgRNA libraries, Cas9‐expressing cell lines, and streamlined sequencing pipelines, have democratized pooled CRISPR screens at genome‐wide scale. Initially, many such screens were survival‐based, identifying essential genes in physiological or perturbed processes. With the application of new chemical biology tools to CRISPR screening, the phenotypic space is no longer limited to live/dead selection or screening for levels of conventional fluorescent protein reporters. Further, the resolution has been increased from cell populations to single cells or even the subcellular level. We highlight advances in pooled CRISPR screening, powered by chemical biology, that have expanded phenotypic space, resolution, scope, and scalability as well as strengthened the CRISPR/Cas enzyme toolkit to enable biological hypothesis generation and discovery. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email