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
Reposted by Chris de Graaf
Reposted by Chris de Graaf
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.
Silence gives consent. And no one should consent to this.
Stand Up And Be Counted
www.science.org
February 12, 2025 at 4:45 PM
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.
Silence gives consent. And no one should consent to this.
Reposted by Chris de Graaf
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...
January 19, 2025 at 4:40 PM
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...
Reposted by Chris de Graaf
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...
Last call for papers. Please repost!
Registration and abstracts (deadline 14 Feb): iccs-nl.org/general-info...
January 17, 2025 at 2:06 PM
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...
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...
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...
www.nature.com
January 10, 2025 at 12:30 PM
#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...
www.nature.com/articles/s41...
Reposted by Chris de Graaf
December 15, 2024 at 12:54 AM
December 15, 2024 at 12:54 AM
Reposted by Chris de Graaf
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 🧪 🏺
December 13, 2024 at 8:27 PM
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 🧪 🏺
Reposted by Chris de Graaf
ChEMBL 35 is out. Happy Holidays!
chembl.blogspot.com/2024/12/here...
chembl.blogspot.com/2024/12/here...
Here's a nice Christmas gift - ChEMBL 35 is out!
Use your well-deserved Christmas holidays to spend time with your loved ones and explore the new release of ChEMBL 35! This fresh...
chembl.blogspot.com
December 12, 2024 at 3:14 PM
ChEMBL 35 is out. Happy Holidays!
chembl.blogspot.com/2024/12/here...
chembl.blogspot.com/2024/12/here...
Reposted by Chris de Graaf
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
- 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
December 9, 2024 at 2:19 AM
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
- 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
Reposted by Chris de Graaf
We keep getting messages saying climate change is a hoax and the world is flat. Is it 2024?!
December 7, 2024 at 11:09 PM
We keep getting messages saying climate change is a hoax and the world is flat. Is it 2024?!
Reposted by Chris de Graaf
Reposted by Chris de Graaf
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
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
November 23, 2024 at 12:32 PM
Reposted by Chris de Graaf
Comparative Ligandability Analysis and new Nomenclature Allosteric GPCR binding sites
pubs.acs.org/doi/10.1021/...
tinyurl.com/ybthux9c
#GPCR #CADD #SBDD #ALLODD
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
November 23, 2024 at 11:00 AM
Comparative Ligandability Analysis and new Nomenclature Allosteric GPCR binding sites
pubs.acs.org/doi/10.1021/...
tinyurl.com/ybthux9c
#GPCR #CADD #SBDD #ALLODD
pubs.acs.org/doi/10.1021/...
tinyurl.com/ybthux9c
#GPCR #CADD #SBDD #ALLODD
Reposted by Chris de Graaf
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
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
November 23, 2024 at 11:56 AM
Reposted by Chris de Graaf
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/...
We'll be discussing this live on Dec 5th from 11 - 12 PM ET.
Join the convo: portal.valencelabs.com/events/post/...
November 25, 2024 at 5:07 PM
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/...
We'll be discussing this live on Dec 5th from 11 - 12 PM ET.
Join the convo: portal.valencelabs.com/events/post/...
Reposted by Chris de Graaf
#CASP16 results are online at the prediction center website - conference starting tomorrow evening.
Have a safe trip - see you soon!
predictioncenter.org/casp16/
Have a safe trip - see you soon!
predictioncenter.org/casp16/
Home - CASP16
predictioncenter.org
December 1, 2024 at 1:29 AM
#CASP16 results are online at the prediction center website - conference starting tomorrow evening.
Have a safe trip - see you soon!
predictioncenter.org/casp16/
Have a safe trip - see you soon!
predictioncenter.org/casp16/
Reposted by Chris de Graaf
More generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
What 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?
November 28, 2024 at 8:12 AM
More generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
Reposted by Chris de Graaf
1) Displace
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
More generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
What 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?
November 28, 2024 at 8:13 AM
1) Displace
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Reposted by Chris de Graaf
2) Stabilise
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
1) Displace
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
More generally (not for HIV protease case specifically) I would propose to consider 4-5 options:
November 28, 2024 at 8:14 AM
2) Stabilise
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Reposted by Chris de Graaf
3) Replace
Polar ligand moiety mimicking energetically favorable water molecule
Polar ligand moiety mimicking energetically favorable water molecule
2) Stabilise
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
1) Displace
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
Energetically unfavorable water in lipophilic region with lipophilic ligand moiety
November 28, 2024 at 8:14 AM
3) Replace
Polar ligand moiety mimicking energetically favorable water molecule
Polar ligand moiety mimicking energetically favorable water molecule
Reposted by Chris de Graaf
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
a) Energetically favorable molecule
b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
3) Replace
Polar ligand moiety mimicking energetically favorable water molecule
Polar ligand moiety mimicking energetically favorable water molecule
2) Stabilise
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
Design favorable ligand-water-protein mediated interaction by introduction polar ligand moiety
November 28, 2024 at 8:15 AM
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
a) Energetically favorable molecule
b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
Reposted by Chris de Graaf
4-5 options/scenarios/sttategies how to deal with water in #SBDD #CADD #MedChem ?
@darrylbmcconnell.bsky.social
@darrylbmcconnell.bsky.social
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
a) Energetically favorable molecule
b) Bulk water/accessible region / no need to expand ligand in this direction unless for eg solubilising groups
3) Replace
Polar ligand moiety mimicking energetically favorable water molecule
Polar ligand moiety mimicking energetically favorable water molecule
November 28, 2024 at 8:17 AM
4-5 options/scenarios/sttategies how to deal with water in #SBDD #CADD #MedChem ?
@darrylbmcconnell.bsky.social
@darrylbmcconnell.bsky.social