… ligand–protein BSA of all molecular glue ternary complex structures. The asymmetry of interactions between the molecular glue and its protein binding partners can guide the understanding of their ternary structure formation.

These analysis should help the field when thinking about how to identify degrading and non-degrading molecular glues in a prospective way. Thank you to co-authors Huan Rui, Jaeki Min, Kate Ashton, and Connie Wang. #TPD #GLUEs #InducedProximity

Analysis of molecular glue-induced ternary structures indicate that there are 2 main pathways of how ternary structure is formed; Path 1) a protein–protein binary interface is formed first and then the complex incorporates a small molecule ligand at the interface or Path 2) small molecule binds to a protein partner first, which leads to altered protein surface properties, much like the effects of post-translational modification, making this surface available for association with another protein

We then analyze the molecular features of these protein-protein interactions, including buried surface area (BSA), interface amino acid preference profiles, residue pair preference profiles, and …

We summarize >100 molecular glue-induced ternary complexes, Group 1) features interactions between proteins with well-folded domains, Group 2) one of the binding partners is a stretch of residues that contains a specific pattern for binding based on interaction mode.

New Today! Induced Proximity group at @Amgen publish in @rsc_chembio on Protein–protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction. https://tinyurl.com/5n95hz79. Main conclusions… 1/thread

… need to wrangle molecule geometries, etc, to achieve productive ubiquitination by unnatural ligase for TPD therapeutics. And thus less chemistry = quicker development. Great example of ever expanding induced proximity modalities. #TPD #proximity #PROTAC #ubiquitin /end

… substrate dependent. So this remains a big open question of how generalizable the concept is. 5) No proteomics shown as to potential impact on binding PSMD2. Presumably the macrocycle is substiocheometric but future studies with small molecules will need to be careful. 6) No…

… evidence provided as to whether BRD4 still needed to be ubiquitinated. This remains a question of mine as it could impact maximize kinetics if reliant on some level of endogenous Ub before degradation. 7) Implications here are large. Skipping ligase would likely mean less…

… 26S proteasome to recruit targets. PSMD2 is natural receptor of ubiquitinated proteins and close to ATPase pore for unraveling substrates. 2) Very impressive use of mRNA display to identify macrocyclic peptides that bind PSMD2. 3) As expected, macrocycles are not very…

Targeted Protein Degradation independent of ubiquitin ligases? Tour de force study from @genentech provides proof of concept through discover of macrocyclic peptide binding PSMD2 and degrading BRD4. Few take aways. 1) Smart choice of where on the… https://www.nature.com/articles/s41589-022-01218-w … 1/n

… permeable. So activity is modest (Dmax 69%) over extended time courses. 4) Degradation only shown with BRD4. Whether more challenging targets will also be degraded is yet to be determined. The importance of polyubiquitination for proteasome-mediated destruction can be…

The authors identify a role for IFITMs proteins in transport of large small molecules into cells. My quick take aways: 1) IFITMs most important for really big SM, beyond PROTAC, 2) effect size is <10 fold, so not the smoking gun, 3) mechanistic studies needed to leverage findings.

Size matters…when it comes to small molecules & cell permeability. But larger small molecules (like bifunctional PROTACs) are still able to get into cells. How you ask? @ScienceMagazine report from @kevansf et al shed some light.
My thoughts on results…. https://www.science.org/doi/10.1126/science.abl5829

Where will the next breakthrough come in Proximity-based, multi-specific small molecules? Use of phosphatase recruiters (PHORCs) got a significant proof of concept nod in recent JACS article describing PP5 recruiting bi-functional molecule to control ASK1 phosphorylation. Key will be target selection where you can win the battle against kinase. https://pubs.acs.org/doi/10.1021/jacs.2c10759

Nice article from Ingo Hartung et al on today's evolution of Lipinski's 25yr old 'rule of 5'. They illustrate how the complexity of oral small molecules has been increasing over the last decade and a new way of thinking is emerging. I thought these lines summed it up brilliantly..."Playing by the rules is thus not always advisable when pushing for success in drug discovery. Rather, successful drug hunters must follow a mindset of pushing the limits of what is possible." https://www.nature.com/articles/s41570-022-00451-0

Wondering just how accurate #AlphaFold models are? Here is a handy chart!

The median error for high-confidence residues is just 0.6 Å!
Caution: 10% are off by over 2 Å.

#AlphaFold predictions are great #hypotheses

@buildmodels @PDBeurope @DeepMind

https://www.biorxiv.org/content/10.1101/2022.11.21.517405v1

@geordifrere Right? Open source allows that.

What #iPhone #app do you use for #Mastodon ?

#Debirdify is now running on the new server, with an average of 1000 interactions (i.e. follower searches etc.) and 600 MB of traffic per hour.

The server is currently handling this load with ease, so hopefully we will be better prepared for the next popularity spike.