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...

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

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!