Elisa Gibson
A5046107533- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- Protein Structure and Dynamics
- Cytokine Signaling Pathways and Interactions
- Animal Virus Infections Studies
- Bioinformatics and Genomic Networks
- Cancer, Hypoxia, and Metabolism
- interferon and immune responses
- Melanoma and MAPK Pathways
- Biofuel production and bioconversion
- SARS-CoV-2 and COVID-19 Research
- Peptidase Inhibition and Analysis
- 14-3-3 protein interactions
- Chemical Synthesis and Analysis
- Air Quality Monitoring and Forecasting
- Medical Imaging Techniques and Applications
- Fermentation and Sensory Analysis
- Tissue Engineering and Regenerative Medicine
- RNA modifications and cancer
- Fungal and yeast genetics research
University of Toronto
2015-2025
Structural Genomics Consortium
2015-2025
Princess Margaret Cancer Centre
2024
University Health Network
2024
Building Bridges
2016
National Academies of Sciences, Engineering, and Medicine
1966
National Research Council Canada
1966
N(6)-methyladenosine (m(6)A) is the most common reversible internal modification in mammalian RNA. Changes m(6)A levels have been implicated a variety of cellular processes, including nuclear RNA export, control protein translation, and splicing, they linked to obesity, cancer, other human diseases. METTL3 METTL14 are N(6)-adenosine methyltransferases that work more efficiently stable METTL3-METTL14 heterodimer complex (METTL3-14). ALKBH5 an m(6)A-RNA demethylase belongs AlkB family...
Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity NSD2 reported numerous cancers, efforts selectively inhibit the catalytic this protein with small molecules have been unsuccessful date. Here, we report development UNC8153, a novel NSD2-targeted degrader that potently and reduces cellular levels both H3K36me2 chromatin mark. UNC8153 contains...
The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field computational hit-finding. Here we report results inaugural challenge which 23 teams each selected up 100 commercially available compounds that they predicted would bind WDR domain Parkinson's disease target LRRK2, with no known ligand and only an apo structure PDB. lack binding data presumably low druggability is hit finding methods. Of 1955 molecules by participants Round 1 challenge,...
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present first antagonists that block protein–protein interaction between N-terminal PWWP domain H3K36me2. Using virtual screening experimental validation, identified small-molecule antagonist 3f, which binds NSD2-PWWP1 a Kd 3.4 μM abrogates histone...
ou non, émanant des établissements d'enseignement et de recherche français étrangers, laboratoires publics privés.
Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present systematic approach to scale up the and characterization small molecule ligands for WD40 repeat (WDR) family. We developed comprehensive suite protocols production, crystallography, biophysical, biochemical, cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection...
Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenges emerged as real-life stress tests for computational hit-finding strategies. In CACHE Challenge #1, 23 participants contributed their original workflows to identify small-molecule ligands the WD40 repeat (WDR) LRRK2, a promising Parkinson's target. We applied FRASE-based robot (FRASE-bot), platform interaction-based screening allowing drastic reduction explorable chemical space and concurrent detection putative...
We report an enantioselective protein affinity selection mass spectrometry screening approach (EAS-MS) that enables the detection of weak binders, informs about selectivity, and generates orthogonal confirmation binding. After method development with control proteins, we screened 31 human proteins against a designed library 8,210 chiral compounds. 16 binders to 12 targets, including many predicted be "challenging ligand", were discovered confirmed in assays. 7 6 targets bound manner, K D s...
A critical assessment of computational hit finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised chemists and data scientists used protein structure from fragment-screening paired with advanced machine learning methods each up 100 inhibitory ligands. Across all teams, 1957 compounds were predicted subsequently procured commercial catalogs...
A critical assessment of computational hit finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised chemists and data scientists used protein structure from fragment-screening paired with advanced machine learning methods each up 100 inhibitory ligands. Across all teams, 1957 compounds were predicted subsequently procured commercial catalogs...
A critical assessment of computational hit finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised chemists and data scientists used protein structure from fragment-screening paired with advanced machine learning methods each up 100 inhibitory ligands. Across all teams, 1957 compounds were predicted subsequently procured commercial catalogs...
Chromatin is more than a simple genome packaging system, and instead locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure / or be ″read″ chromatin-associated proteins to mediate downstream events. An accurate understanding of PTM binding preference vital explain normal function pathogenesis, has revealed multiple therapeutic opportunities. Such studies most often use peptides, even though these cannot represent the full...
PR domain-containing protein 7 (PRDM7) is a primate-specific histone methyltransferase that the result of recent gene duplication PRDM9. The two proteins are highly homologous, especially in catalytic PR/SET domain, where they differ by only three amino acid residues. Here we report PRDM7 an efficient selectively catalyzes trimethylation H3 lysine 4 (H3K4) both vitro and cells. Through selective mutagenesis have dissected functional roles each divergent residues between domains These studies...
ABSTRACT The CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field computational hit-finding. Here we report results inaugural #1 challenge which 23 teams each selected up 100 commercially available compounds that they predicted would bind WDR domain Parkinson’s disease target LRRK2, with no known ligand and only an apo structure PDB. lack binding data presumably low druggability is hit finding methods. Seventy-three 1955 procured...
The leucine-rich repeat kinase 2 (LRRK2) is the most mutated gene in familial Parkinson’s disease, whose mutations lead to pathogenic hallmarks of disease. LRRK2 WDR domain an understudied drug target for disease with no known inhibitors prior first phase Critical Assessment Computational Hit-Finding Experiments (CACHE) Challenge. CACHE challenges are designed attract state-of-the-art computational methods both hit-finding and optimization small molecule challenging protein targets. A unique...
Abstract RBBP4 and RBBP7 (RBBP4/7) are highly homologous nuclear WD40 motif containing proteins widely implicated in various cancers valuable drug targets. They interact with multiple within diverse complexes such as NuRD PRC2, well histone H3 H4 through two distinct binding sites. FOG-1, PHF6 bind to the top of donut shape seven-bladed β-propeller fold, while SUZ12, MTA1 a pocket on side repeats. Here, we briefly review these six interactions present assays optimized for medium high...
Abstract Protein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment computation to enable ligands WD40 repeat (WDR) proteins, one the largest human families. This resource includes expression clones, purification protocols, comprehensive assessment druggability hundreds WDR proteins. We solved 21 high resolution crystal structures,...
Recent advances in DNA-encoded library (DEL) screening have created bioactivity datasets containing billions of molecules, unlocking new opportunities for machine learning (ML) drug discovery. However, most ultra-large DEL libraries are proprietary, limiting the advancement ML tools big chemical data analytics and hindering democratization DEL-ML technology. We address this gap by developing an open, end-to-end framework using public datasets, where enriched binders represented common...
Non-structural protein 2 (nsP2), which plays an essential role in replication of CHIKV, contains a protease, helicase, and methyltransferase-like domain. We executed simple screen using malachite green to detect compounds that decreased ATP hydrolysis tested library diverse find inhibitors CHIKV nsP2 helicase.