Joseph Kim

Docking 14 Million Virtual Isoquinuclidines against the μ and κ Opioid Receptors Reveals Dual Antagonists–Inverse Agonists with Reduced Withdrawal Effects Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These “natural-product-like” molecules are rare in current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the μ- and κ-opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low μM affinities. Structure-based optimization revealed low- and sub-nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent joint MOR-antagonist and KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying the MOR-selective antioverdose agent naloxone. Encouragingly, the isoquinuclidine induced less severe opioid-withdrawal symptoms versus naloxone and did not induce conditioned-place aversion, reflecting reduced dysphoria, consistent with its KOR-inverse agonism. The strengths and weaknesses of bespoke library docking and of docking for opioid receptor polypharmacology will be considered.

Delighted to share the final version of this co-first author publication from my first postdoc project. Thank you to everyone involved for the mentorship and collaboration! pubs.acs.org/doi/10.1021/...

The End of Disease

Thoughts on Demis Hassabis of Google DeepMind saying that AI could cure disease in general in ten years.

Bonus index to my longer posts on AI/computational drug discovery over nearly 20 years!

Reducing the effects of radiation damage in cryo-EM using liquid helium temperatures | PNAS The physical limit in determining the atomic structure of biological molecules is radiation damage. In electron cryomicroscopy, there have been num...

After years parked at a Polara, I’m excited to share that my PhD work is finally out! We figured out why imaging at liquid helium temperatures wasn’t working—and how to fix it.
🔗 www.pnas.org/doi/10.1073/...

Happy to share our manuscript on the in situ visualization of the copia retrotransposon in its final form today published in @cellcellpress.bsky.social www.cell.com/cell/fulltex.... What’s new?

It's definitely a part of my workflow now, cause so far it's been one of the most impactful non-3D reconstruction data processing changes that I can make.

A Spatial Interactome Reveals the Protein Organization of the Algal CO2-Concentrating Mechanism Microscopy and proteomic analyses reveal three previously unknown layers of the pyrenoid, the cellular organelle in algae responsible for one-third of global CO2 fixation

Not to that degree as far as I can tell sadly, but my impression has been that whenever a group looks at a particular network/organelle within Chlamydomonas by mass spec or cultured under specific conditions, they find a lot:

www.sciencedirect.com/science/arti...

www.cell.com/cell/fulltex...

Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are domin...

Hi everyone! I am thrilled to share my first publication while in @amanglik.bsky.social's lab! I performed the biochemistry and structural work for compounds that had antagonistic opioid receptor polypharmacology. Congratulations to everyone involved in this project!
www.biorxiv.org/content/10.1...

I disagree a little bit - if mass spec suggests anything, I think Chlamy is already highly dense, we're just not imagining what is possible based on current tools. I figure @cellarchlab.com is constantly finding new things every time they go through their data, especially when tools evolve.

That stereotypical arrangement will also be a huge advantage in making sure the sample was prepared correctly, something I don't think enough people are addressing when it comes to cellular cryo-ET work (blebbing, fragmentation, etc).

I (very loudly) wanted to stand up and shout 'THANK YOU' when he said that

Hi Cornelius, could you please add me as well? Many thanks!

Congratulations José! Always a pleasure to work with you in the Manglik lab at USCF! @amanglik.bsky.social

Well done Matt! DMS is such a powerful way to study GPCRs

Molecular basis of proton sensing by G protein-coupled receptors Three proton-sensing G protein-coupled receptors (GPCRs)—GPR4, GPR65, and GPR68—respond to extracellular pH to regulate diverse physiology. How proton…

Groundbreaking work by @matthewkhoward.bsky.social and Nicholas Hoppe (not on bsky?) from the @willowcoyote.bsky.social @amanglik.bsky.social labs.

Mapping function to structure with deep mutational scanning to resolve the mechanisms of pH sensing GPCRs

www.sciencedirect.com/science/arti...

Check out the magnificent #baculovirus structure! The unique virion architecture and structural atlas of hallmark proteins place baculo-like viruses into a separate new realm. Many insights into baculo biology and evolution. Collab with the group of Fasséli Coulibaly. www.science.org/doi/10.1126/...

The vagus nerve's prominent role in brain-gut, brain-immune system, brain-body interactions
Figure from www.scientificamerican.com/article/how-...

Take a look at my personal perspective on the past, present, and future of in situ structural biology with cryo-ET+

While initially skeptical about the genre, I found it fun to write and hopefully, you can enjoy my experiences and some thoughts. Nice weekend y'all

www.cambridge.org/core/journal...

Multi-species cryoEM calibration and workflow verification standard YouTube video by International Union of Crystallography

Our newest Interviews with Authors episode is online! We chat with Daija Bobe, Jessalyn Miller and Ed Eng (@edwardteng.bsky.social) from the New York Structural Biology Center about their paper "Multi-species #cryoEM calibration and workflow verification standard". www.youtube.com/watch?v=DB83...

Hi Ute, I would like to be a part of this as well, thank you!