Leiden Early Drug Discovery & Development (LED3)

Great talk by Cristina Lopez Gallego from the group of Marcellus Ubbink of our @led3hub.bsky.social of @leidenscience.bsky.social at #NWOCHAINS. She talked about the study of second sphere residues and their effect on the structure, dynamics and function of beta-lactamases.

#Biochemistry #Evolution

Insightful talk by Bob van Puffelen from the groups of Jeroen Codee and Dima Filippov @leidenadpr.bsky.social of the @led3hub.bsky.social at #NWOCHAINS. He talked about a glycan modification of the bacterial flagellum and how they use synthetic tools to study its biosynthesis.
#ChemSky #ChemBio

Excited that Yorick van Aalst represented our group of the @led3hub.bsky.social with a talk at #NWOCHAINS. He talked about mining #AlphaFold structures of the entire proteome for pockets and using this information to prioritize hits from #Chemoproteomic screens.
#ChemSky #ChemBio #ProudPI

@seanmckenna.bsky.social represented the group of @sebastianpomplun.bsky.social and the @led3hub.bsky.social with an exciting talk at #NWOCHAINS. He talked about using a combination of in silico screening and semi-automated synthesis to accelerate #DrugDiscovery.
#ChemSky #ChemBio

Interesting talk by Foteini Skoulikopoulou of the group of @armstrongchembio.bsky.social of the @led3hub.bsky.social at #NWOCHAINS. She talked about her research into the synthesis of stable 9-O-acetylated sialic acid mimics with potential applications as #antivirals.

#glycotime #ChemSky #ChemBio

Very happy that @marnixroseboom.bsky.social represented our group of the @led3hub.bsky.social with a very well-attended talk at #NWOCHAINS. He reported on his #PhD work on developing #ChemoProteomics technologies to study #CovalentInhibitor target engagement at arginines.

#ChemSky #ChemBio #ProudPI

"Rapid Antibiotic Discovery using a Direct-to-Biology Approach"

Storm van der Voort from the group of Hermen Overkleeft and our group at the @led3hub.bsky.social presented his research into efficiently finding new antibacterially active #CovalentInhibitors and their targets.

#ChemSky #ChemBio

Great talk by Floor Stevens from the group of @mvdstelt.bsky.social of our @led3hub.bsky.social at #NWOCHAINS. She talked about her research into "Discovery of a novel metabolic pathway for N-acylethanolamines by cytosolic glucosylceramidase 2".
#Chemistry #ChemBio #LipidTime #Glycotime

Insightful talk by Anthe Janssen at #NWOCHAINS. He talked about his research with Dompé in the framework of #ChemistryNL on using #docking and #MachineLearning-assisted re-scoring to better predict compound binding affinity to #kinases.
pubs.acs.org/doi/10.1021/...
#ChemSky #ChemBio #DrugDiscovery

"Novel Covalent Inhibitors and Where to Find Them"

I was very excited that Madeline Kavanagh, Marc Baggelaar, Rita Petracca and I were awarded a focus session at #NWOCHAINS. We had an amazing program with talks by Marta Artola, Kevin Neumann and Dieuwertje Streefkerkand a panel discussion. (1/3)

Great talk by Marta Artola at #NWOCHAINS. She talked about the use of modified sugars as inhibitors and molecular #chaperones in #DrugDiscovery. Great insights into the use of cyclic sulfamates and sulfamidates as reactive groups for #CovalentInhibitors
pubs.acs.org/doi/10.1021/...
#ChemSky #ChemBio

A truly inspiring @led3hub.bsky.social Lecture by Lotte Bjerre Knudsen. Amazing insights into the discovery of GLP-1 agonists like #semiglutide (Ozempic, Wegovy) at @novo-nordisk.bsky.social and their applications to treat #Diabetes, #Obesity and #CardiovascularDisease www.nature.com/articles/s41...

We are very happy that Lotte Bjerre Knudsen from @novo-nordisk.bsky.social visited us today for a very well-attended LED3 Lecture. She talked about the development of GLP-1 agonists into blockbuster medications for the treatment of #diabetes and #obesity.

#DrugDiscovery #Peptides #ChemBio #ChemSky

Visualizing the Invisible: Dual Click Imaging of Ruthenium-Based Photoactivated Chemotherapy Agents and Their DNA Synthesis Inhibition in Fixed Cancer Cells Like many drugs, ruthenium-based photoactivated chemotherapy (PACT) complexes are hard to follow in cells due to their absence of emissive properties. Here, two alkyne-functionalized Ru-based PACT compounds with the formula [Ru(HCC-tpy)(N̂N)(Hmte)](PF6)2 were synthesized, where HCC-tpy = 4′-ethynyl-2,2′:6′,2″-terpyridine, N̂N = 3,3′-biisoquinoline (i-biq, [2](PF6)2) or di(isoquinolin-3-yl)amine (i-Hdiqa, [4](PF6)2), and Hmte = 2-(methylthio)ethanol. Their challenging synthesis involved a protection–deprotection strategy to avoid the reaction of the free alkyne group with the coordinatively unsaturated ruthenium center. The thermal stability and photosubstitution quantum yield (Φ[2] = 0.022 and Φ[4] = 0.080) of the PACT complexes were essentially preserved upon alkyne functionalization. Interestingly, however, cellular uptake was doubled after alkyne functionalization, resulting in increased cytotoxicity against A549 cancer cells for both complexes in the dark and after green light activation (EC50,light = 5 and 7 μM, respectively). To follow the complexes and see the effect of light activation, post-treatment fluorophore labeling via copper-catalyzed azide–alkyne cycloaddition was realized in fixed cells at 2 different time points, which allowed for imaging the otherwise invisible molecules. The images showed that the Ru complexes accumulated in the cytoplasm only after light irradiation and that they colocalized with the lysosomes and the Golgi apparatus. Moreover, we combined this approach with metabolic labeling of DNA, and showed by dual click imaging that DNA replication was inhibited by complex 4. The strategy described herein, pioneered for nonemissive, photosubstitutionally active ruthenium complexes, opens a new avenue for investigating the selective attack of lung cancer cells by PACT.

Interesting paper by the group of Sylvestre Bonnet of our @led3hub.bsky.social in JACS. They synthesized alkyne derivatives of Ruthenium complexes that are used for photoactivated chemotherapy and used them to identify their location in the cell after photoactivation.

Great to see our Nature Chemistry paper out in its final published and printed form.

If you want to check it out, you can find it here: www.nature.com/articles/s41...

#ChemSky #ChemBio #ChemicalProteomics #Chemoproteomics #ProteoProbes #ChemPro

We have another absolute highlight in our @led3hub.bsky.social Lecture series coming up.

Next week, Lotte Bjerre Knudsen from Novo Nordisk will visit us to present on the development of GLP-1 receptor agonists.

If you are interested, make sure to come by.

#ChemBio #ChemSky #DrugDiscovery

We are looking forward to the LED3 Lecture of Lotte Bjerre Knudsen from Novo Nordisk on November 27th: "GLP-1 receptor agonists: State of the art and the newest insights"

If you are interested, make sure to come by!

www.universiteitleiden.nl/en/science/l...

#ChemBio #ChemSky #DrugDiscovery

Barcode-free hit discovery from massive libraries enabled by automated small molecule structure annotation - Nature Communications Affinity-selection platforms are powerful tools in early drug discovery, but current technologies such as DNA-encoded libraries (DELs) are limited by synthesis complexity and incompatibility with nucl...

Are you excited about DNA-encoded libraries?
According to this new study by the @sebastianpomplun.bsky.social group of our LED3 hub, you may even get away without needing the DNA barcode. They describe self-encoded libraries (SELs) for #DrugDiscovery.
www.nature.com/articles/s41...
#ChemSky #ChemBio

Evaluating BindCraft for Generative Design of High-Affinity Peptides Discovering high-affinity ligands directly from protein structures remains a key challenge in drug discovery. BindCraft is a structure-guided generative modeling platform able to de novo design miniproteins with a high affinity for a large set of targets. While miniproteins are valuable research tools, short peptides offer substantially greater therapeutic potential. However, given their lack of stabilized tertiary structures, de novo generation of functional peptides is a remarkable challenge. Here, we show that BindCraft is able to generate high affinity peptides, solely based on target structure, with remarkable success rates. For the oncoprotein MDM2, BindCraft generated 70 unique peptides; 15 were synthesized, and 7 showed specific binding with nanomolar affinities. Competition assays confirmed site-specific binding for the intended target site. For another oncology target, WDR5, six out of nine candidates bound the MYC binding WBM site with submicromolar affinity. Bindcraft’s high fidelity structure prediction enabled one shot peptide optimization via rational chemical modification, improving the potency of one WDR5 binder by 6-fold to a KD of 39 nM. BindCraft also generated candidate peptides for targeting PD-1 and PD-L1. However, none of the tested peptides showed detectable binding. Together, these results establish a first evaluation of BindCraft for peptide binder prediction. Despite remaining limitations, this tool shows the potential to rival display technologies in delivering high-affinity ligands for therapeutic development.

Are you interested in peptide-based #DrugDiscovery?

Check out the newest study by the group of @sebastianpomplun.bsky.social of our @led3hub.bsky.social. Being able to predict peptide binders solely based on structure may be closer than you think.

pubs.acs.org/doi/10.1021/...
#ChemSky #ChemBio

Evaluating BindCraft for Generative Design of High-Affinity Peptides Discovering high-affinity ligands directly from protein structures remains a key challenge in drug discovery. BindCraft is a structure-guided generative modeling platform able to de novo design miniproteins with a high affinity for a large set of targets. While miniproteins are valuable research tools, short peptides offer substantially greater therapeutic potential. However, given their lack of stabilized tertiary structures, de novo generation of functional peptides is a remarkable challenge. Here, we show that BindCraft is able to generate high affinity peptides, solely based on target structure, with remarkable success rates. For the oncoprotein MDM2, BindCraft generated 70 unique peptides; 15 were synthesized, and 7 showed specific binding with nanomolar affinities. Competition assays confirmed site-specific binding for the intended target site. For another oncology target, WDR5, six out of nine candidates bound the MYC binding WBM site with submicromolar affinity. Bindcraft’s high fidelity structure prediction enabled one shot peptide optimization via rational chemical modification, improving the potency of one WDR5 binder by 6-fold to a KD of 39 nM. BindCraft also generated candidate peptides for targeting PD-1 and PD-L1. However, none of the tested peptides showed detectable binding. Together, these results establish a first evaluation of BindCraft for peptide binder prediction. Despite remaining limitations, this tool shows the potential to rival display technologies in delivering high-affinity ligands for therapeutic development.

Looking for a high-affinity #peptide binder for your favorite target?

According to the newest paper by the group of @sebastianpomplun.bsky.social, the software tool #BindCraft allows you to predict such binders with high success rates.

pubs.acs.org/doi/10.1021/...
#ChemSky #ChemBio #DrugDiscovery

Great @leidenscience.bsky.social Tuesday Talk by Ilze Bot of the @led3hub.bsky.social. She talked about her group's work into better understanding the involvement of #inflammation in the development of #atherosclerosis and its implications for therapy.
www.sciencedirect.com/science/arti...

Interesting Tuesday Talk at @leidenscience.bsky.social by Ilze Bot of our LED3 hub. Under the title "Breaking the cycle of heart attacks", she talked about her research into, why heart attacks are still a big threat, even in patients receiving treatment.
#ChemSky #ChemBio #DrugDiscovery

Very happy that Storm van der Voort - PhD in the group of Hermen Overkleeft and in our group - was selected for a talk at the #Reedijk Symposium. He gave an excellent presentation on using direct-to-biology to efficiently make covalent libraries for antibacterial screening
#ChemSky #ChemBio #ProudPI

Insightful talk by Jeroen Codee at the #Reedijk Symposium. He talked about the importance of synthetic organic chemistry to make complex glycans to better understand #glycobiology. Very impressive, systematic work on glycosylation reactions. pubs.rsc.org/en/content/a...
#ChemSky #ChemBio #Glycotime

Jeroen Codee speaks at the #Reedijk Symposium: "A new twist in the tale - stereoselective glycosylation reactions for bacterial glycan assembly". Exciting insights into the importance of advanced glycosylation chemistries to make complex glycosides to better understand (bacterial) biology.

Inspiring #Havinga Medal lecture by @craigmcrews.bsky.social at the #Reedijk Symposium. Amazing to hear him talk about the full story of the development of induced proximity into a new paradigm of event-driven pharmacology for #DrugDiscovery.
www.nature.com/articles/s41...
#ChemSky #ChemBio #TPD

Huge congratulations to @craigmcrews.bsky.social on being awarded the #Havinga medal at the #Reedijk Symposium of the Leiden Institute of Chemistry for his groundbreaking work on induced proximity, including targeted protein degradation, as a new paradigm for #DrugDiscovery.
#ChemSky #ChemBio #TPD

Great talk by @kimmb1.bsky.social of our @led3hub.bsky.social at the #Reedijk Symposium. She talked about the power of activity-based probes to study protein function on the example of live cell imaging of myeloperoxidase activity to study NETosis. www.nature.com/articles/s42...
#ChemBio #ChemSky

Kim Bonger (@kimmb1.bsky.social) represents our @led3hub.bsky.social at the #Reedijk Symposium of the Leiden Institute of Chemistry with a great talk on "Chemical tools for profiling protein activity and cell targeting in (auto)immune disease".
#ChemBio #ChemSky #DrugDiscovery #FluorescenceFriday

I was very happy to host Nicolas Winssinger today for a well-attended @led3hub.bsky.social Lecture.
He gave us exciting insights into the power of nucleic acid assemblies. Very exciting data on a highly selective thrombin inhibitor that can be switched off on demand. www.nature.com/articles/s41...