Great The Scientist piece: two harmful mutations can restore protein function—challenging how we view genetic risk. I share my take on the structural logic behind this and relevance to drug discovery. My perspective www.the-scientist.com/two-harmful-... Original study www.pnas.org/doi/10.1073/...

Two Harmful Variants Can Restore Protein Function

Researchers found that paired pathogenic variants can restore protein function rather than make it worse. This phenomenon could occur in four percent of human genes.

the-scientist.com

Check out our new paper introducing V2P — a method that predicts both variant pathogenicity and disease phenotype across 23 HPO categories. With @itanlab.bsky.social, David Stein, and many other great collaborators www.nature.com/articles/s41... www.v2p.ai

Expanding the utility of variant effect predictions with phenotype-specific models - Nature Communications

V2P predicts variant pathogenicity conditioned on disease phenotypes across top-level Human Phenotype Ontology categories. This approach shows promise for phenotype-specific estimation of variant effe...

nature.com

Congrats, @itanlab.bsky.social and David! So happy to see it published

Yuval Itan@itanlab.bsky.social · 8mo ago

V2P (variant-to-phenotype) is live: nature.com/articles/s41... To our knowledge, first genomewide SNVs+indels model jointly predicting pathogenicity + disease domain (23 HPO groups; e.g. cardiac/immune/metabolic). Great work by David Stein in collaboration with @schlessingerlab.bsky.social

Very comprehensive work on the modulation of mu opioid receptor

Marta Filizola@martafilizola.bsky.social · 10mo ago

Our new work with Daniel Wacker’s Lab: not only do structurally different PAMs of the mu #opioid receptor bind at different sites but their modulatory mechanisms also differ as assessed by molecular #dynamics and information theory validated by functional experiments www.biorxiv.org/content/10.1...

Check out this great @cenmag.bsky.social piece by @aayushipratap.bsky.social on how AI is transforming drug discovery. Our work at Mt. Sinai’s AI Small Molecule Drug Discovery Center is featured among others driving this fast-moving field. 🔗 tinyurl.com/sabpvrtp #AI #DrugDiscovery

How AI is taking over every step of drug discovery

Academic scientists and pharmaceutical companies alike are embracing artificial intelligence, even as questions linger about its value

cen.acs.org

Interesting read: Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1 www.cell.com/cell/abstrac...

Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1

Structures of the solute carrier transporters MCT8 and OATP1C1 reveal mechanisms of thyroid hormone transport into the brain and identify a conserved extracellular allosteric site in OATP1C1.

cell.com

David Baker's Nobel Prize-winning lab has now designed binders to "undruggable" disordered proteins, unlocking therapeutic access to over 50% of the human proteome! ‪@uwproteindesign.bsky.social‬ Read more at GEN: tinyurl.com/4fw6wvkm

Undruggable No More: AI Hits Disordered Proteins, Unlocks Therapy Targets

David Baker’s lab has successfully designed binders to disordered proteins, expanding therapeutic access to over 50% of the human proteome.

tinyurl.com

Excited to see our new AI Small Molecule Drug Discovery Center #MountSinai featured in GEN! 🧬🧠 Read more: genengnews.com/topics/artif... Thank you @faylinphd.bsky.social #AI #DrugDiscovery #Genetics

Democratizing Artificial Intelligence in Pre-Clinical Drug Discovery

While AI-driven approaches tout increased speed and lower costs, commercial interests compromise scientific collaboration.

genengnews.com

Proposed pH-dependent mechanism of the mitochondrial pyruvate carrier. In the outward-open state, positively charged K49 and H86 bind pyruvate, initiating conformational changes to the inward-open state. The high matrix pH deprotonates H86, allowing pyruvate to leave. www.science.org/doi/10.1126/...

We are excited to present the first #cryoEM structures of human GABA transporter 3 – GAT3 – bound to an in-house selective inhibitor, SR-THAP, to substrate GABA, and in the substrate-free state! @biorxivpreprint.bsky.social www.biorxiv.org/content/10.1...

Structural basis for selective inhibition of human GABA transporter GAT3

The astrocytic γ-aminobutyric acid (GABA) transporter, GAT3, is essential for terminating GABAergic signalling in the central nervous system. Selective inhibition of GAT3 offers a potential strategy f...

biorxiv.org

Are you aiming for leadership roles in pharmaceutical, biotech, high tech, or medical device companies? Consider applying to the revamped MSBS program @GradSchoolSinai @IcahnMountSinai, featuring 1 or 2-year tracks and non-thesis options tailored for industry professionals

Safeguarding the future of biomedical science in the United States: Cell www.cell.com/cell/fulltex...

Safeguarding the future of biomedical science in the United States

NIH’s abrupt decision to cap indirect cost reimbursement at 15% threatens the critical infrastructure supporting groundbreaking biomedical research in the United States. This policy jeopardizes Americ...

cell.com

At @GradSchoolSinai @IcahnMountSinai, we are excited to train the next generation of #datascience and #AI #professionals for #PrecisionMedicine @MountSinaiNYC and beyond. Apply here: icahn.mssm.edu/education/ad...

Changes in the equilibrium dynamics of kinases can be observed as mutations and ligands are introduced. Authors describe & apply a workflow that combines AF2+MSA subsampling, molecular dynamics simulations, and an autoencoder for dimensionality reduction www.biorxiv.org/content/10.1...

Another outstanding story of the real-world impact of the short-sighted cuts to NIH and other federal support for the best scientific research infrastructure in the world. www.wsj.com/articles/bio...

🚀 #AlphaFold Database update AlphaFold DB now integrates The Encyclopedia of Domains (TED) – a resource designed to systematically identify & classify structural domains within AlphaFold-predicted protein structures. www.ebi.ac.uk/about/news/u... @pdbeurope.bsky.social

Francis Collins, the NIH Director for 12 years, led the Human Genome Project and other NIH efforts for 32 years, resigned today. Key words from his resignation letter www.nytimes.com/2025/03/01/u...

This is a fantastic meeting for the Cryo-EM community in the NYC area. This year it will take place on the East Coast of Manhattan. Please come and join us!

Oli Clarke@olibclarke.bsky.social · last yr.

Registration is now open for the 2025 NYC CryoEM meeting, organized by Bill Rice (NYU) & @fravallese.bsky.social (CUNY/ASRC) Always a great meeting with lots of new #cryoem work by rising stars in/around NYC Max 140 people so register now (it’s free)!

This is an excellent article that accurately describes the situation with NIH funding. Great work @zey.bsky.social ! www.nytimes.com/2025/02/11/o...

Opinion | The Pharmaceutical Industry Heads Into Elon Musk’s Wood Chipper (Gift Article)

Who needs N.I.H. grants? A lot of red-state universities, for one.

nytimes.com

Good morning snowy NYC

If you work in drug discovery and you read one thing this weekend, make it this exceptional J Med Chem editorial. Hits on almost every blessed thing I’ve tweetorialized over the last several years. Quantitation and Error Measurements in Dose–Response Curves

Quantitation and Error Measurements in Dose–Response Curves

pubs.acs.org

Want to become a professor? A huge analysis looks at how criteria assessing researchers for promotion vary widely around the world, and finds some surprises 🧪 www.nature.com/articles/d41...

Want to become a professor? Here’s how hiring criteria differ by country

Huge analysis identifies regional variations in the criteria that institutions use to move researchers up the ranks.

nature.com