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LLMs for Computational Drug Design

Ash Jogalekar @ashjogalekar.bsky.social · 4d

New post: LLMs for Computational Drug Design
The continuing saga medchemash.substack.com/p/llms-for-c...

The continuing saga

Ash Jogalekar @ashjogalekar.bsky.social · 5d

Once again we find out that AI algorithms are based on memorization of training set cases rather than any kind of understanding. This makes them brittle and unable to adapt to new cases (of which there are many). I think a hybrid approach would probably work best.

Ash Jogalekar @ashjogalekar.bsky.social · 5d

In a nutshell: the authors perturb the binding site of known protein-ligand binding modes in a variety of ways, most of which should have abolished binding. But the AI algorithms (Boltz-1, Chai-1, AF3) still place the ligands in the exact same pose, ignoring clashes and forming spurious interactions

First principles remain important

Ash Jogalekar @ashjogalekar.bsky.social · 5d

New post about a very interesting new paper: When it comes to predicting protein-ligand binding, AI don't trump physics. medchemash.substack.com/p/ai-dont-tr...

AI don't trump physics

Frustrated PROTACs: Exceptions or the rule?

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Ash Jogalekar @ashjogalekar.bsky.social · 6d

RFK Jr. for "advances in vaccine innovation." Hits too close to home though.

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Ash Jogalekar @ashjogalekar.bsky.social · 6d

New post: Frustrated PROTACs: Exceptions or the rule? Aka discomfort may be productive. medchemash.substack.com/p/frustrated...

Discomfort may be productive

From descriptive to quantitative biocatalysis - Nature Catalysis

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Reposted by Ash Jogalekar

Kresten Lindorff-Larsen @lindorfflarsen.bsky.social · 19d

From descriptive to quantitative biocatalysis

“The 1913 study ‘Die Kinetik der Invertinwirkung’, by Michaelis and Menten, marked a pivotal advancement in enzymology by illustrating the application of mechanistic models and quantitative kinetics to biocatalysis.”

doi.org/10.1038/s419...

The 1913 study ‘Die Kinetik der Invertinwirkung’, by Michaelis and Menten, marked a pivotal advancement in enzymology by illustrating the application of mechanistic models and quantitative kinetics to biocatalysis. The foundational framework described back then continues to have a strong impact on enzymology, with profound influences that range from undergraduate education to structure–function studies and the format and content of contemporary kinetic databases.

doi.org

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Ash Jogalekar @ashjogalekar.bsky.social · 19d

Will read the paper, but does "folding-docking-affinity prediction" indicate a co-folding method? Because those are new.

Code, not Drugs: The LLM Revolution in Computational Drug Design

Ash Jogalekar @ashjogalekar.bsky.social · 19d

Forget “AI discovering drugs”, as I say in this post, coding for computational drug design is where the AI/LLM revolution is. medchemash.substack.com/p/code-not-d...

Process before product

The statistical is not the practical

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Ash Jogalekar @ashjogalekar.bsky.social · Sep 12

The statistical is not the practical:
A guide to gauging the real world significance of computational methods
medchemash.substack.com/p/the-statis...

A guide to gauging the real world significance of computational methods

Highly Position- and Enantioselective Catalytic Epoxidation of Polyolefins Mediated by a Chiral Mn Complex, Including a One-Step Conversion of Squalene to the (S)-2,3-Epoxide, a Precursor of Natural S...

Ash Jogalekar @ashjogalekar.bsky.social · Sep 12

Amazing to see Corey still publishing at age 97! pubs.acs.org/doi/abs/10.1...

Reported herein is the synthesis of a novel chiral dicarboxylic ligand for Mn(II) and the application of the Mn complex to the highly enantio- and position-selective epoxidation of C═C under mild cond...

pubs.acs.org

The Sarin shortcut: How AI lowers the bar for chemical weapons

Ash Jogalekar @ashjogalekar.bsky.social · Sep 4

That was an unhinged, foul-mouthed performance even by Measles F. Kennedy Jr.’s standards.

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Reposted by Ash Jogalekar

Bulletin of the Atomic Scientists @thebulletin.org · Sep 4

"Since I take solace in the belief that God looks after drunks, little children, and the USA, I still think maybe, somehow, out of chaos will come something good." —Graham Allison

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Reposted by Ash Jogalekar

Bulletin of the Atomic Scientists @thebulletin.org · Aug 25

Generative AI and off-the-shelf computational tools can make the synthesis and use of nerve agents for nefarious purposes more probable.

"The Sarin shortcut: How AI lowers the bar for chemical weapons," by @ashjogalekar.bsky.social. ⬇️

Generative AI and off-the-shelf computational tool can make the synthesis and use of nerve agents for nefarious purposes more probable.

thebulletin.org

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Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

Things math and facts are for losers. Winners simply use their imagination.

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Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

We gave our infant son one literally the other day because the doctor showed us data on a COVID summer surge. I personally know at least two people who just got it last week from travel. We are living in the shadow of an administration who would deny the sky is blue.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

Sheep who vote for a wolf because they think he will only eat other sheep.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

10/ The key message is that we can use the same tools that are used to do harm to fight that harm. If AI is used by bad actors to design WMDs, AI can also be used to defeat or anticipate that misuse.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

9/ Ultimately this is a classic dual-use dilemma: these tools are hugely beneficial for doing good, but as Feynman once put it, the same key that opens the doors of heaven can open the doors of hell.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

8/ The fix: Shift to living lists updated in real time, integrate AI into threat prediction, and partner with AI developers that can anticipate and not just react to emerging threats. Organizations like the OPCW should adopt a "function first" approach.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

7/ Policy problem: The Chemical Weapons Convention lists are static, structure-based, and slow. It took 27 months to list Novichok after its first known use. AI won’t give us that kind of lead time.

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

6/ LLMs make these workflows easier than ever. No coding, no special licenses, just prompt engineering to stitch together pathways, assays, and even equipment sourcing. RDKit is already part of chatGPT. More open-source tools will undoubtedly be embedded.

Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands

Ash Jogalekar @ashjogalekar.bsky.social · Aug 25

5/ Computational chemistry can be inverted, maximizing instead of minimizing toxicity in drug discovery or agricultural chemistry programs. No repurposing of existing algorithms is needed. For instance in 2010 I compared docking algorithms for AHR binders www.sciencedirect.com/science/arti...

The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organisms and is responsible for interacting with several d…

www.sciencedirect.com