Peter Zhiping Zhang

Peter Zhiping Zhang, Jeffrey D. Varner

In silico tools are important for generating novel hypotheses and exploring alternatives in de novo metabolic pathway design. However, while many computational frameworks have been proposed for retrobiosynthesis, few successful examples of algorithm-guided xenobiotic biochemical retrosynthesis have been reported in the literature. Deep learning has improved the quality of synthesis and retrosynthesis in organic chemistry applications. Inspired by this progress, we explored combining deep learning of biochemical transformations with the traditional retrobiosynthetic workflow to improve in silico synthetic metabolic pathway designs. To develop our computational biosynthetic pathway design framework, we assembled metabolic reaction and enzymatic template data from public databases. A data augmentation procedure, adapted from literature, was carried out to enrich the assembled reaction dataset with artificial metabolic reactions generated by enzymatic reaction templates. Two neural network-based pathway ranking models were trained as binary classifiers to distinguish assembled reactions from artificial counterparts; each model output a scalar quantifying the plausibility of a 1-step or 2-step pathway. Combining these two models with enzymatic templates, we built a multistep retrobiosynthesis pipeline and validated it by reproducing some natural and non-natural pathways computationally.

Yang Qiao, Bo Pan, Hao-Wei Pang et al.

Molecular optimization in drug discovery aims to discover molecules with improved target properties, but practical lead optimization often requires more than high predicted scores. A useful candidate should also be actionable: it should be reachable from known molecules through valid local structural transformations, so that it can be interpreted as a plausible revision within an evolving chemical series. Existing de novo and single-molecule optimization methods do not explicitly model such reachability, especially when both the target molecules and the intermediate molecules connecting them to known compounds are unknown. In this work, we formulate actionable molecular optimization as sequential expansion of a molecule-transfer graph, where nodes are molecules and edges encode valid local transformations. We propose MolWorld, a molecule world model-guided framework that treats the current molecule-transfer graph as an evolving search state. At each iteration, MolWorld selects local anchor contexts, generates candidate molecules conditioned on these contexts, evaluates their properties, and uses a learned world model to update the evolving molecule world by retaining admissible candidates and inserting them into the molecule-transfer graph. The expanded molecule world then guides subsequent optimization. Experiments on property optimization and docking-based tasks show that MolWorld discovers high-property molecules while maintaining substantially stronger structural connectivity, supporting actionable and sequential molecular design.

Bo Pan, Peter Zhiping Zhang, Hao-Wei Pang et al.

Matched molecular pairs (MMPs) capture the local chemical edits that medicinal chemists routinely use to design analogs, but existing ML approaches either operate at the whole-molecule level with limited edit controllability or learn MMP-style edits from restricted settings and small models. We propose a variable-to-variable formulation of analog generation and train a foundation model on large-scale MMP transformations (MMPTs) to generate diverse variables conditioned on an input variable. To enable practical control, we develop prompting mechanisms that let the users specify preferred transformation patterns during generation. We further introduce MMPT-RAG, a retrieval-augmented framework that uses external reference analogs as contextual guidance to steer generation and generalize from project-specific series. Experiments on general chemical corpora and patent-specific datasets demonstrate improved diversity, novelty, and controllability, and show that our method recovers realistic analog structures in practical discovery scenarios.