  Molecular representation learning lays the foundation for drug discovery.
However, existing methods suffer from poor out-of-distribution (OOD)
generalization, particularly when data for training and testing originate from
different environments. To address this issue, we propose a new framework for
learning molecular representations that exhibit invariance and robustness
against distribution shifts. Specifically, we propose a strategy called
``first-encoding-then-separation'' to identify invariant molecule features in
the latent space, which deviates from conventional practices. Prior to the
separation step, we introduce a residual vector quantization module that
mitigates the over-fitting to training data distributions while preserving the
expressivity of encoders. Furthermore, we design a task-agnostic
self-supervised learning objective to encourage precise invariance
identification, which enables our method widely applicable to a variety of
tasks, such as regression and multi-label classification. Extensive experiments
on 18 real-world molecular datasets demonstrate that our model achieves
stronger generalization against state-of-the-art baselines in the presence of
various distribution shifts. Our code is available at
https://github.com/HICAI-ZJU/iMoLD.
