ANNalog

ANNalog is a SMILES-to-SMILES generative model for medicinal chemistry analogue design.

• Paper (ChemRxiv): https://chemrxiv.org/doi/10.26434/chemrxiv-2025-9c1v6

ANNalog is a transformer-based sequence-to-sequence (Seq2Seq) model designed to generate medicinal-chemistry-relevant analogues of an input molecule. It supports:

• local chemical-space exploration (small, SAR-like modifications), and
• scaffold hopping (changing the core scaffold while remaining chemically relevant).

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Dependencies / environment (recommended)

A tested dependency set is provided in seq2seq_environment.yml in this repo (recommended for reproducibility).

Notes:

• The PyPI package does not pin or install PyTorch for you. Please install a PyTorch build that matches your system (CPU/CUDA).
• The provided conda YAML is the recommended environment for ANNalog generation and includes the required chembl-gen-check dependency.
• chembl-gen-check requires Python >=3.10; the provided environment targets Python 3.12.

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Google Colab page

A place where you could try to generate some molecules online: https://colab.research.google.com/drive/1aJhaBOG7xuYFwMGzfUmbMsLe8T462Ptc#scrollTo=Ss1QOzXjzKSP

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Installation

Option A — Install from PyPI (recommended for “just use it”)

pip install numpy==2.4.2 pandas==3.0.1 tqdm==4.67.3 torch==2.10.0 torchvision==0.25.0 rdkit==2025.09.6 scikit-learn==1.8.0 annalog

After installation, you can use the installed CLI:

annalog-generate -h

Option B — Install from GitHub (recommended for development / editing code)

git clone https://github.com/DVNecromancer/ANNalog.git
cd ANNalog

Conda (recommended):

conda env create -f seq2seq_environment.yml
conda activate <env_name_from_yml>
pip install -e .

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Generating molecules

You have two ways to generate:

1. Installed CLI (works after pip install annalog): annalog-generate ...
2. Repo script generation.py (works from a cloned repo; easy to modify)

Both share the same core options:

• decoding methods: beam, BF-beam, sampling
• exploration modes: normal, variants, recursive
• post-generation structural checking with --check / --no-check (on by default)
• TSV/CSV output

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Decoding methods (what they mean)

-m beam

Classical beam search. Keeps the top-k partial sequences at each decoding step.

-m BF-beam

Best-first beam search. Expands the current best partial sequence while keeping unexplored partial sequences in memory. This is usually slower and more memory-hungry than classical beam search.

-m sampling

Samples each next token from the model probability distribution.

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Exploration methods (what they mean)

-e normal (default)

Generate directly from the input SMILES.

-e variants

1. Create --variant-number SMILES variants of the same molecule by randomizing atom order and writing non-canonical SMILES (i.e., different syntactic representations of the same structure).
2. Run generation from each variant and pool all results.

-e recursive

Run generation in multiple rounds. In round 1 you generate from the input SMILES.
In round 2, you generate again using the round-1 outputs as new inputs, and so on for --loops rounds.

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Main generation options

• --temperature: sampling temperature. Higher values increase diversity; lower values make sampling more conservative. Used only with -m sampling.
• --seed: random seed for reproducible sampling. Used only with -m sampling.
• --prefix: fixed starting prefix for generation. This can be either:
  • an integer number of starting characters taken from the beginning of the current input SMILES, or
  • a literal starting string that must match the beginning of the current input SMILES.
• --keep-invalid: keep invalid generated SMILES instead of filtering them out.
• --max-length: maximum generated sequence length.
• --variant-number: number of variants to create in -e variants mode.
• --loops: number of recursive rounds in -e recursive mode.
• --check / --no-check: enable or disable chembl-gen-check annotation of generated SMILES. Checking is on by default.

chembl-gen-check is a lightweight structural sanity-check package for rapid verification of scaffold, generic scaffold (here reported as skeleton), and ring-system precedent in ChEMBL, and it can also report structural alerts and LACAN-related uncommon-bond information.

Reference: chembl-gen-check (PyPI)

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A) Using the installed CLI (PyPI / installed package)

Help:

annalog-generate -h

Quick start (single SMILES, beam, 50 outputs; checks on by default):

annalog-generate -i "CCO" -n 50 -m beam -o gen.tsv

Sampling (10 outputs):

annalog-generate -i "CC(Cl)Br" -n 10 -m sampling --temperature 1.2 --seed 42 -o gen.tsv

Variants exploration:

annalog-generate -i "CCO" -n 20 -e variants --variant-number 10 -o gen_variants.tsv

Recursive exploration (2 loops):

annalog-generate -i "CCO" -n 10 -e recursive --loops 2 -o gen_recursive.tsv

Disable structural checking:

annalog-generate -i "CCO" -n 50 -m beam --no-check -o gen_no_check.tsv

You can also invoke the same CLI via Python module form:

python -m annalog.cli -i "CCO" -n 50 -o gen.tsv

Resources (ckpt + vocab):

• For the installed CLI, the checkpoint + vocab are shipped inside the package and used by default.
• You can still override them if needed using --resources-dir or --checkpoint/--vocab.

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B) Using the repo script (generation.py)

From the repo root (after pip install -e .), you can run:

python generation.py -h

Note about resources in the repo:
In this repository the checkpoint/vocab live under:

annalog/ckpt_and_vocab/

So when running generation.py, point it explicitly:

python generation.py \
  -i "CCO" \
  -n 50 \
  -m beam \
  --resources-dir annalog/ckpt_and_vocab \
  -o gen.tsv

Disable structural checking:

python generation.py \
  -i "CCO" \
  -n 50 \
  -m beam \
  --no-check \
  --resources-dir annalog/ckpt_and_vocab \
  -o gen_no_check.tsv

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Output format

The output file always includes these base columns:

• input_smiles
• rank (1-based)
• generated_smiles
• score

By default, structural checking is enabled, so five additional columns are also appended:

• check_scaffold
• check_skeleton
• check_ring_systems
• check_structural_alerts
• check_lacan

If you use --no-check, the output contains only the four base columns.