ReMedI: Inference-Time Refinement and Self-Distillation for Controllable Molecular Optimization

Jia Yi Zhang, Shivanshu Shekhar, Allison McLevige, Tong Zhang

In drug development, lead optimization must improve competing properties, such as increasing permeability and reducing toxicity, while limiting scaffold changes that could compromise the lead's potency. RL-based post-training, such as C-MORAL, addresses this problem by fine-tuning molecular language models to directly optimize molecular leads for objectives of interest, which relies on expensive task-specific datasets and faces challenges in achieving multi-objective optimization (MOO). We argue a pre-trained model may already contain useful molecular edits that zero-shot generation cannot efficiently reach. Motivated by the limited search capabilities of zero-shot generation, we develop an efficient Metropolis-Hastings search strategy to better explore the proposal distribution. We propose ReMedI, which uses the molecular language model as a base proposer for inference-time alignment. Given a lead and a set of multi-objective tasks, the model proposes edits conditioned on the current molecule, while Metropolis--Hastings refinement guides sequential edits under an objective for property improvement, preservation, and lead similarity. On both C-MuMOInstruct and SMDD benchmarks,…