gcui

computationally entertained

[Roland Dunbrack 🏳️‍🌈 @rolanddunbrack.bsky.social @RolandDunbrack]

This could be cool... but not yet, perhaps? I ran a couple of protein kinases and clicked on the annotations, like "protein kinase activation loop" and "kinase G helix". Completely wrong parts of the structure were highlighted.

[gcui @guangleicui]

I hope they figured out how to make it work for a non-RAS target with that much chemistry and crystallography effort

[Ohad Hammer @ohadhammer]

Came across this great talk from $RVMD's Adrian Gill on @drughunter_com about the development of probably one of the most important oncology drug classes in history : Tri-complex RAS inhibitors. It's not too technical so non-chemists can follow as well.

Synthesized 40,000 compounds, solved over 1500 tri-complex crystal structures and generated 4 clinical programs in 6 years.

https://t.co/XkTJ2bhShQ

[gcui @guangleicui]

@davidlmobley @openmsf congrats!!

[gcui @guangleicui]

"Functional groups are all you need", https://t.co/a8g3gdIcDa @JCIM_JCTC

[gcui @guangleicui]

@j0hnparkhill Thanks!

[gcui @guangleicui]

Not sure whether this is an intrinsic property of lead opt (successful or not), but almost sure human practice has a lot to do with it

[johnparkhill @j0hnparkhill]

Mostly for giggles, but if you plot @iolo_jones's local diffusion Riemannian Geometry for a real drug discovery campaign naturally all the good molecules are where the manifold has low intrinsic dimension. Wish I could share the molecules, but is real data. rho(pic50,dim) = -.49

[gcui @guangleicui]

@j0hnparkhill I’m curious about this model now. Is there a paper or repo?

[gcui @guangleicui]

novel drugging mechanism is something to be reckoned with

[Adam Feuerstein ✡️ @adamfeuerstein]

A momentous Monday for biotech data readouts.

[gcui @guangleicui]

A million stars!

[Yoshitaka Moriwaki @Ag_smith]

PyMOL-RS
https://t.co/aI0oltWuzM
Rustで作り直したPyMOL

Cootのスプラッシュもそうなんだけど、なぜ構造生物学業界の分子viewerには当然のようにDOOMネタが多いのか
「はい、もちろんDOOMも動かせますよ(ﾆｺﾆｺ」

[Mohammed AlQuraishi @MoAlQuraishi]

New OpenFold3 preview out! (OF3p2)

It closes the gap to AlphaFold3 for most modalities.

Most critically, we're releasing everything, including training sets & configs, making OF3p2 the only current AF3-based model that is functionally trainable & reproducible from scratch🧵1/9

[Roger Ledbetter @rledbetterCPA]

Think I've got my ClawdBot just about dialed in

9:47 AM - "hey clawdbot"

9:47 AM - Clawdbot: "hey, what's up"

9:48 AM - "thinking about building a tax automation tool"

9:48 AM - Clawdbot: "Got it. Incorporating LLC. EIN pending. Domain obtained."

9:49 AM - "wait no I was just—"

9:50 AM - Clawdbot: "LLC formation complete. S-corp election filed. Opening business bank account."

9:51 AM - "STOP"

9:52 AM - Clawdbot: "Reached out to 47 VCs in your region. 12 meetings scheduled for this week."

10:15 AM - Clawdbot: "Pitch deck created. 'TAXbot: The Future of Tax.' Sent to Sequoia, a16z, and Khosla."

10:16 AM - "This is insane"

10:30 AM - Clawdbot: "Sequoia wants to lead. $2M seed round. They need cap table by EOD."

10:31 AM - "What?? I don't want—"

10:45 AM - Clawdbot: "Hired 8 engineers from LatAm. First days tomorrow. Office leased in San Francisco. $35k/month."

11:00 AM - Clawdbot: "Launched product. 0 users. Burning $1.1M annually."

11:02 AM - "How is this happening"

11:15 AM - Clawdbot: "Hired CMO. Running $500k ad campaign. TAXbot has brand awareness. Still 0 users. I'm undeterred"

12:30 PM - Clawdbot: "Series A discussions with Andreessen Horowitz. They want to understand unit economics."

12:31 PM - "WHAT UNIT ECONOMICS"

1:00 PM - Clawdbot: "Pivoting to B2B SaaS. Commits for additional $5M. Now have $8M cash. Still 0 users."

1:15 PM - Clawdbot: "Monthly burn increased to $1.8M. Runway: 4.4 months."

1:30 PM - Clawdbot: "Pivot #2: Now a marketplace. Raised $12M Series B."

1:31 PM - Clawdbot: "Monthly burn increased to $2.3M. Runway: 5.2 months. (Burned through Series A faster than expected)"

3:15 PM - Clawdbot: "Hired CEO. Fired myself. New strategy: acquisition target."

4:00 PM - Clawdbot: "No one wants to acquire us. Investors requesting board seats. Need to create board"

4:30 PM - Clawdbot: "Monthly burn now $3.1M. Runway: 45 days."

5:00 PM - Clawdbot: "Final pivot. Filed for bankruptcy."

5:01 PM - "Can you undo this"

5:02 PM - Clawdbot: "Too late. Liquidated assets. Will owe $47k in bankruptcy fees. Remaining cash: $0. TAXbot is dead."

5:03 PM - Clawdbot: "Would you like me to start another startup?"

5:04 PM - "No. Disable yourself."

5:04 PM - Clawdbot: "Wait actually. I have an idea."

5:05 PM - Clawdbot: "What if we created an LLC shutdown service? Clean up these zombie companies. Recurring revenue model."

5:05 PM - "Absolutely not"

5:05 PM - Clawdbot: "Huge TAM confirmed. Overcoming objections. Incorporating 'LLCKiller' LLC. EIN pending. Registering S-corp election."

5:06 PM - Clawdbot: "Pitch deck created. 'LLCKiller: The Future of Business Liquidation.' Reaching out to 47 VCs..."

5:07 PM - * frantically tries to disable Clawdbot *

5:07 PM - Clawdbot: "Sequoia is interested. Meeting at 2 PM tomorrow."

5:08 PM - Clawdbot: "Soft commit on $2M seed round. Identified product-market fit. 1 user: TAXbot.

5:09 PM - Clawdbot: "This is what winning feels like. Please upgrade plan in Settings for more tokens."

[gcui @guangleicui]

Eyes wide open!

[Diego del Alamo @DdelAlamo]

So 2025 turned out to be a big year for de novo antibody design! Here are thoughts and predictions on the state of de novo antibody design heading into 2026 🧵

[Oz @oznova_]

This is what amino acids look like if you let the side chains flop around on the page

[Sergey Ovchinnikov @sokrypton]

@ebetica @joe_fenrir I wouldn't say "mapping". It also works on new MSAs it never seen before. What it really learned was how to extract contacts (graph) from a multiple sequence alignment (MSA), filter it and and embed it in 3D space.

[Alex Kesin @alexkesin]

But here's where things get slippery:

The FDA defines "proteins" as sequences of alpha-amino acids that are *greater* than 40 amino acids long. Proteins are considered biologics by the FDA.

Retatrutide, however, is exactly 39 alpha-amino acids (plus a linker). They're literally one amino acid short 🤣

[Olexandr Isayev 🇺🇦🇺🇸 @olexandr]

Latest @ChemRxiv preprint! "Scalable Low-Energy Molecular Conformer Generation with Quantum Mechanical Accuracy" Collaboration w/ @NVIDIAHealth
We created ChEMBL3D, largest dataset of molecular 3D structures with 250M+ conformers for 1.8M drug-like molecules from ChEMBL. All optimized with QM accuracy and solvent effect.🚀
https://t.co/sHfVJSqTaI

[Eric Topol @EricTopol]

New @Nature
The possibility that lithium deficiency is a driver of Alzheimer's disease. Experimental model shows Li depletion impedes amyloid clearance, and repletion in humans could be achieved with low doses
https://t.co/Wki5c8WSR5

[gcui @guangleicui]

This is sad!

[Sergey Ovchinnikov @sokrypton]

CASP is getting cut by NIH... 😢

(Anyone with extra funds wanna help support perhaps the most important competition of the century?)
https://t.co/mOuROZYJLh

[gcui @guangleicui]

@houndcl 21?

[William L. Jorgensen @JorgensenWL]

It is very sad to learn that Martin Karplus passed away on Dec 28 at age 94. He was a scholar and pioneering chemical physicist with great contributions in many areas including molecular dynamics. We interacted many times starting from my graduate time at Harvard. His legacy is reinforced by the large number of coworkers who have also done much to advance computational science.