Chris de Graaf
@cdg-gpcr.bsky.social
Head of Computational Drug Discovery and Data Science at Structure Therapeutics | GPCR | SBDD | CADD | Cheminformatics | Computational Chemistry | Medicinal Chemistry | Drug Design
Closing the loop on #GenAI for #GPCR #SBDD www.nature.com/articles/s41... tinyurl.com/yeyhfr7j
Identification of nanomolar adenosine A2A receptor ligands using reinforcement learning and structure-based drug design - Nature Communications
Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A2A adenosine receptor ligands and solve their crystal stru...
nature.com
Closing the loop on #GenAI for #GPCR #SBDD www.nature.com/articles/s41... tinyurl.com/yeyhfr7j
Identification of nanomolar adenosine A2A receptor ligands using reinforcement learning and structure-based drug design - Nature Communications
Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A2A adenosine receptor ligands and solve their crystal stru...
nature.com
Biopharma companies and CEOs are keeping their heads down at their own peril. They should speak up about what’s happening to the NIH and other science agencies before it’s too late. Silence gives consent. And no one should consent to this.
Stand Up And Be Counted
science.org
Protein backbone diffusion models consistently undersample catalytically important motifs, and oversample idealized helices, raising questions about the appropriateness of these methods in designing starting points for enzyme design & evolution. From www.biorxiv.org/content/10.1...
If you are interested in #AI and #DrugDiscovery, attend the upcoming ICCS June 1st - Jun 5th in Noordwijkerhout! Last call for papers. Please repost! Registration and abstracts (deadline 14 Feb): iccs-nl.org/general-info...
#StructuralBiology insights into #Genetic #GPCR variations identified in the UK 100,000 Genomes Project with differentiating effects on peptide (affected) vs. small molecule agonists (not affected) #pharmacology www.nature.com/articles/s41...
Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor - Nature Communications
This study explores apelin receptor’s role in cardiovascular function, identifying residues critical for binding through genetic variants, AlphaFold2 modelling and base editing in cardiomyocytes. Co-c...
nature.com
Analysis of the oldest-known genomes from early modern humans in Europe, who lived around 45,000 years ago, helps to provide a more precise date for when Neanderthals and modern humans mixed, according to research published in Nature. https://go.nature.com/3ZR8Kh1 🧪 🏺
new preprint on chemical synthesis ML models - showing how to combine multiple models in a principled way - modern Transformers + GNN to featurize chemical reaction: - new insights in where the models shine + bonus: find the quirky named reaction! Feedback welcome! arxiv.org/abs/2412.05269
Chimera: Accurate retrosynthesis prediction by ensembling models with diverse inductive biases
Planning and conducting chemical syntheses remains a major bottleneck in the discovery of functional small molecules, and prevents fully leveraging generative AI for molecular inverse design. While ea...
arxiv.org
We keep getting messages saying climate change is a hoax and the world is flat. Is it 2024?!
Comparative Ligandability Analysis and new Nomenclature Allosteric GPCR binding sites pubs.acs.org/doi/10.1021/... tinyurl.com/ybthux9c #GPCR #CADD #SBDD #ALLODD
Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential
The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations of allosteric modulation, and yet few drugs target them. This gap highlights the...
pubs.acs.org
Closing the CADD AI SBDD loop - From GPCR structures to RNN de novo drug design and back again! chemrxiv.org/engage/chemr... #GPCR #AI #RNN #CADD #SBDD
Modern hit-finding with structure-guided de novo design: identification of novel nanomolar adenosine A2A receptor ligands using reinforcement learning
Generative chemical language models have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based drug design (SBDD) princi...
chemrxiv.org
The first paper from the Small Molecule Steering Committee at Polaris introduced practical guidelines for method comparison in ML-driven drug discovery. We'll be discussing this live on Dec 5th from 11 - 12 PM ET. Join the convo: portal.valencelabs.com/events/post/...
#CASP16 results are online at the prediction center website - conference starting tomorrow evening. Have a safe trip - see you soon! predictioncenter.org/casp16/
Home - CASP16
predictioncenter.org
More generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
Darryl B McConnell@darrylbmcconnell.bsky.social · 2y agoWhat to do with waters in drug discovery is one of the most important decisions that drug designers need to make. What would you do with the FLAP water on HIV protease? Address or Replace?
1) Displace Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Chris de Graaf@cdg-gpcr.bsky.social · 2y agoMore generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
2) Stabilise Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago1) Displace Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
3) Replace Polar ligand moiety mimicking energetically favorable water molecule
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago2) Stabilise Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
4) Leave alone a) Energetically favorable molecule b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago3) Replace Polar ligand moiety mimicking energetically favorable water molecule
4-5 options/scenarios/sttategies how to deal with water in #SBDD #CADD #MedChem ? @darrylbmcconnell.bsky.social
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago4) Leave alone a) Energetically favorable molecule b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
Happy Thanksgiving to those celebrating! Here's some relevant chemistry for the day: www.compoundchem.com/2017/11/23/t... #ChemSky 🧪
4-5 options/scenarios/sttategies how to deal with water in #SBDD #CADD #MedChem ? @darrylbmcconnell.bsky.social
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago4) Leave alone a) Energetically favorable molecule b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
4) Leave alone a) Energetically favorable molecule b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago3) Replace Polar ligand moiety mimicking energetically favorable water molecule
3) Replace Polar ligand moiety mimicking energetically favorable water molecule
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago2) Stabilise Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
2) Stabilise Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Chris de Graaf@cdg-gpcr.bsky.social · 2y ago1) Displace Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
