Bryan Roth

The selectivity implications of docking libraries with greater and lesser similarities to bio-like molecules - PubMed As virtual libraries have expanded into the tens of billions via make-on-demand chemistry, their similarity to metabolites, natural products, and drugs ("bio-like" molecules) has rapidly diminished. Despite this divergence, molecular docking of these ultra-large libraries has yielded molecules at hi …

Must read for computational folks:
" these results may suggest that selectivity against off-targets, like affinity and hit-rates for on-targets, is divorced from library similarity to bio-like molecules."
pubmed.ncbi.nlm.nih.gov/41676518/

Structure-based design of an opioid receptor modulator for enhanced morphine analgesia - PubMed The alarming rates of deaths due to opioid overdose present an urgent need for safer opioid analgesics. Positive allosteric modulators (PAMs) of opioid receptors (ORs) offer a promising approach to enhance opioid efficacy while reducing risks of overdose. In this study, we unveil the selective mecha …

New paper of interest!
pubmed.ncbi.nlm.nih.gov/41671375/
"Structure-based design of an opioid receptor modulator for enhanced morphine analgesia"
PAMs for the win (PAM=positive allosteric modulator)

Here's the way to test the 2A -specific hypothesis:
1. Pretreat humans with pimavanserin and see if it blocks the therapeutic effects of psilocybin (clinical trial link: clinicaltrials.gov/study/NCT065... )
2. Create 2A-agonists for depression and test in humans (My lab is very close to this)

Defined media reveal the essential role of lipid scavenging in supporting cancer cell proliferation - PubMed Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understandin …

Re: media. I've not tried this and the paper focuses on lines with driver mutants that therefore shouldn't need growth factors, but would love someone to show if hek293, cho, etc. perform well with this composition.

pubmed.ncbi.nlm.nih.gov/40930249/

If only we knew which aspects of the polypharmacology to keep and what to discard

Mirtazepine, trazodone and nefazodone are FDA approved 5-HT2A antagonist antidepressants; mianserin is/was approved in Europe and is another one

New lab logo from former postdoc Dewran

New lab logo from former postdoc Dewran

Why do I do science? For the über-Nerds only...

Why do you do science @superkash.bsky.social @mbeisen.bsky.social @odedrechavi.bsky.social ?
Here are my unvarnished thoughts:
open.substack.com/pub/zendudes...

Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin Sympathetic nerves regulate skin immunity by engaging keratinocytes to modulate the density of tissue-resident memory T cells. This neuro-epithelial axis can enable the nervous system to dynamically t...

Nice review!
Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin: Cell www.cell.com/cell/fulltex...

A triple-node heart-brain neuroimmune loop underlying myocardial infarction This study explores the dissection of a neuroimmune pathway involving the sensory vagus nerve, the hypothalamic paraventricular nucleus, and the sympathetic superior cervical ganglia underlying myocar...

A triple-node heart-brain neuroimmune loop underlying myocardial infarction: Cell www.cell.com/cell/fulltex...

A triple-node heart-brain neuroimmune loop underlying myocardial infarction This study explores the dissection of a neuroimmune pathway involving the sensory vagus nerve, the hypothalamic paraventricular nucleus, and the sympathetic superior cervical ganglia underlying myocar...

A triple-node heart-brain neuroimmune loop underlying myocardial infarction: Cell www.cell.com/cell/fulltex...

Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance - Nature Metabolism Neri et al. develop elegant tools to understand how the sympathetic nervous system regulates intrascapular brown adipose tissue (iBAT) function. Using these tools, they find that sympathetic nerves ta...

cool!
Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance
www.nature.com/articles/s42...

Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target Or5v1/Olfr110, a high-affinity odor receptor, detects an oxylipin signal to boost liver fat burning and glucose control, and a synthetic agonist can amplify this metabolic benefit.

Wow!
www.cell.com/cell/abstrac...

Revisiting the SSRI-TRKB Mechanism: Lack of Evidence for Interaction in the Human Brain https://www.biorxiv.org/content/10.64898/2026.01.07.698082v1

Principles of protein abundance regulation across single cells in a mammalian tissue Protein synthesis and clearance are major regulatory steps of gene expression, but their in vivo regulatory roles across the cells comprising complex tissues remains unexplored. Here, we systematicall...

It includes results from this preprint:

www.biorxiv.org/content/10.1...

What is the computational role of dendritic excitations? Byung Hun Lee and team mapped voltage dynamics throughout the dendritic trees of CA1 pyramidal neurons in mice navigating in virtual reality. www.biorxiv.org/content/10.6...

An NTS-expressing inhibitory circuit from interpeduncular nucleus to dorsal raphe nucleus controls pain and comorbid depression in male mice Song et al. find a subpopulation of neurotensin (NTS)-expressing neurons in the interpeduncular nucleus (IPN) that co-release NTS and GABA in the dorsal raphe nucleus, and they demonstrate the neurons...

An NTS-expressing inhibitory circuit from interpeduncular nucleus to dorsal raphe nucleus controls pain and comorbid depression in male mice: Cell Reports www.cell.com/cell-reports...

The medial shell of nucleus accumbens regulates chronic pain and comorbid depression via separate downstream targets in male mice Xia et al. reveal two separate pathways that regulate chronic pain and comorbid depression. They demonstrate that NAcMedD1-MSNs regulate comorbid depressive symptoms via the NAcMedD1-MSNs→MD circuit, ...

The medial shell of nucleus accumbens regulates chronic pain and comorbid depression via separate downstream targets in male mice: Cell Reports www.cell.com/cell-reports...

The sigma enigma revealed:
www.nature.com/articles/s41...

The Quiet Power of Program Officers How invisible decisions shape what science gets done—and whether it matters

This is an outstanding essay describing some of the important roles and influences of NIH program officers (from an insider perspective).

Read!

elizabethginexi.substack.com/p/the-quiet-...

YouTube video by Xylo Bio Is the 5-HT2A Receptor the Key to Psychedelic Effects?

A fun interview about the polypharmacology of #psychedelics
www.youtube.com/watch?v=v4kn...

Postdoctoral fellowship available in structure guided drug discovery in @RothLabUNC
Please RT

Postdoctoral fellowship available in structure guided drug discovery in @RothLabUNC
Please RT

Psilocybin decreases reward-seeking behavior accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex https://www.biorxiv.org/content/10.64898/2025.12.22.696123v1

YouTube video by Xylo Bio Is the 5-HT2A Receptor the Key to Psychedelic Effects?

A fun interview about the polypharmacology of #psychedelics
www.youtube.com/watch?v=v4kn...

Mapping cellular targets of covalent cancer drugs in the entire mammalian body vCATCH is a volumetric tissue labeling technique enabling cellular-resolution mapping of covalent drug targets throughout the entire mammalian body.

Mapping cellular targets of covalent cancer drugs in the entire mammalian body: Cell www.cell.com/cell/fulltex...

Neurochemical and Neurophysiological Effects of Intravenous Administration of N,N-Dimethyltryptamine in Rats N , N -dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans...

Neurochemical and Neurophysiological Effects of Intravenous Administration of N,N-Dimethyltryptamine in Rats www.jneurosci.org/content/earl...

The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice - Molecular Psychiatry Molecular Psychiatry - The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice

New paper drop! 🧠💊 Our new paper out in Molecular Psychiatry shows that the serotonin 1B receptor is important for the neural and antidepressant/anxiolytic behavioral responses to psilocybin in mice.

www.nature.com/articles/s41...

Lysergic acid diethylamide pretreatment prolongs brain-stimulation induced neural activity https://www.biorxiv.org/content/10.64898/2025.12.16.694720v1