Venue suggestions

Venue Recommendations

as_is

bioRxiv (or equivalent preprint server)

• This manuscript is already suitable for preprint circulation at its current quality. The editor's verdict of "minor" with a confidence-weighted score of 4.24/5 reflects sound science that needs clarification rather than fundamental repair. A preprint will reach the relevant community (chemical biology, ion channel pharmacology, proteomics methods) immediately while revisions are underway, and the public review model of In Silico or similar venues works well for preprints. The work is sufficiently complete and the claims sufficiently well-supported that it does not need to be held pending revisions.

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after_revision

Nature Methods or Nature Chemical Biology

• Once the required revisions are completed—particularly the scoping of the "basal sparing" claim to heterologous systems, the quantification of brainocyte-versus-lysate/slice comparisons, and the animal-level replication accounting for the slice recordings—this manuscript will be competitive for a high-tier methods or chemical biology venue. The panel's unanimous confidence in the chemistry, proteomics design (enantiomeric controls, pre-specified thresholds, 4–6 replicates), and electrophysiology, combined with the two substantial follow-ups (DPYSL2 complexoform-restricted liganding and HCN CNBD modulation), positions it well. The methodological contribution (ABPP in intact primary brain cells) is novel and the HCN ligands offer a differentiated pharmacological tool. Nature Methods would emphasize the platform; Nature Chemical Biology would emphasize the ligand discovery and functional validation. Acceptance odds post-revision: ~40–50% at either venue, conditional on the slice-data reconciliation being handled transparently.

Cell Chemical Biology

• A strong fit for the revised manuscript. The journal explicitly welcomes chemical proteomic methods, covalent ligand discovery, and functional validation in native tissue. The DPYSL2 complexoform-restricted liganding and the HCN CNBD modulation both exemplify the journal's scope. The required revisions (particularly quantifying brainocyte-unique hits and reconciling the basal-activity claim) are well within the journal's tolerance for nuanced, tissue-dependent pharmacology. Acceptance odds post-revision: ~55–65%.

Science Translational Medicine (if HCN epilepsy angle is emphasized)

• The manuscript's discussion of HCN1 pathogenic variants and the partial rescue of gain-of-function phenotypes by WX-02-679 opens a translational pathway. However, this would require reframing the paper to lead with the epilepsy application rather than the methods platform, and the current evidence (two variants tested, partial rescue of one severe variant) is preliminary for a translational venue. Only pursue this if the authors have additional in vivo or patient-derived data; otherwise, it risks overstatement. Acceptance odds post-revision if reframed: ~20–30%.

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alternative

Journal of Biological Chemistry or Molecular & Cellular Proteomics

• Solid secondary venues if the primary targets decline. JBC would emphasize the HCN functional work and the PDE7B AKAP complex findings; MCP would emphasize the proteomics platform and the CNS-enriched ligandability map. Both are well-regarded, have rapid review cycles, and are read by the relevant communities. Acceptance odds post-revision: ~70–75% at either venue.

eLife

• A reasonable fallback with a high bar but strong support for methods papers and multi-modal validation. The transparent reporting of limitations (acknowledged in the Discussion) and the public review model align well with eLife's ethos. The work is sufficiently novel and well-executed to be competitive. Acceptance odds post-revision: ~45–55%.

bioRxiv (permanent preprint with versioning)

• If the authors choose not to pursue journal publication immediately, a versioned preprint with the required revisions will serve the community well. The open-review model of In Silico (if the authors submit there) or a permanent preprint with a detailed response to the editor's letter will provide the transparency and traceability that the field values. This is a legitimate endpoint for high-quality methods work, particularly if the authors release the stereoprobes, cell lines, and datasets openly.

Specialized venues (if narrowing scope):

• Epilepsia or Neurology Today (if the HCN1 epilepsy angle is developed further with in vivo or clinical data).
• ACS Chemical Neuroscience (if the focus shifts to CNS-penetrant ligand optimization and in vivo pharmacokinetics).
• Frontiers in Molecular Neuroscience (open-access, rapid, good reach in the neuroscience community; lower barrier to acceptance post-revision).

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Notes on fit and confidence

Why the primary targets are realistic post-revision: The editor's verdict reflects a well-controlled study whose central claims are supported once scoped appropriately. The panel's unanimous confidence in the chemistry and electrophysiology, the multi-modal validation (gel-ABPP, protein-directed ABPP, cysteine-directed ABPP, heterologous patch clamp, inside-out patch clamp, native slice recordings), and the transparent acknowledgement of limitations (e.g., the Discussion's explanation of reduced Ih in slices) all signal that this is publishable science. The required revisions are clarifications and quantifications, not new experiments or fundamental reinterpretations.

Why In Silico itself is not listed as a primary target: In Silico is an overlay journal that reviews preprints; it is not a traditional submission venue. The authors should post to bioRxiv (or similar) first, then optionally submit to In Silico for public review. The current manuscript is suitable for that workflow.

Confidence caveats:

• Acceptance at Nature Methods or Nature Chemical Biology depends critically on how transparently the authors handle the basal-activity claim. If the revision reads as defensive or minimizes the slice findings, reviewers at those venues will penalize it. If it reads as honest (heterologous systems show sparing; native tissue shows a different phenotype; here is why), it will be competitive.
• The animal-level replication accounting for the slice recordings is a hard requirement for any venue. If the authors find that the effects weaken substantially at the animal level, the appropriate response is to report that transparently and adjust claims accordingly—not to hide it. Venues will respect that more than a polished but unaccounted-for result.
• The brainocyte-uptake confound is real and the required quantification will likely show that some of the brainocyte-unique hits are detection artifacts. That is not a flaw; it is a boundary condition that strengthens the paper by being explicit about it.