On Improving Graph Neural Networks for QSAR by Pre-training on Extended-Connectivity Fingerprints

Molecular property prediction requires representations that generalize from limited labeled data to structurally novel compounds. Existing molecular pretraining methods often rely on a single view: graph-based approaches model atom-bond topology but provide limited fragment-level supervision, whereas fingerprint descriptors encode chemical patterns but are typically used as fixed auxiliary features. We propose HiFi-Mol, a multi-view framework that separately pretrains a hierarchical graph encoder and a contextualized fingerprint encoder before downstream integration. The graph branch uses fragment-aware masking with multi-resolution supervision to capture substructure-aware representations, while the fingerprint branch tokenizes active entries from seven fingerprint families and applies masked language modeling to learn contextualized embeddings. During fine-tuning, HiFi-Mol combines projected multi-resolution graph features with fingerprint embeddings for downstream prediction. Evaluated on MoleculeNet benchmarks under the scaffold split, HiFi-Mol achieves a 2.77% improvement in average ROC-AUC over the best baseline across eight classification tasks while maintaining competitive performance on three regression tasks. Further analyses reveal that fragment-aware masking improves graph representation quality, and classification results demonstrate dataset-dependent strengths of the individual graph and fingerprint variants, confirming that the two views provide complementary predictive signals.

Graph Neural Networks (GNNs) have achieved strong results in molecular property prediction, but polymers present distinct challenges: labeled datasets are scarce and small (typically in the order of hundreds of polymers) due to the need for expensive experimentation, and complex polymer chain distributions influence polymer properties. Established practice in polymer prediction represents polymers solely by graphs of their repeat units, discarding the chain-scale morphology that governs key properties such as the glass transition temperature ($T_g$). In this work, we propose a principled graph construction that addresses this gap. Given a polymer's molecular mass distribution (MMD), we sample representative chains from the Schulz-Zimm distribution and construct representative sets of large graphs encoding chain-scale topology directly, with atoms and bonds featurized using rich chemical descriptors. We further pretrain GNN encoders via masked graph modeling on 100,000 unlabeled PSMILES strings before fine-tuning on labeled data. On a dataset of 381 polymers (180 homopolymers and 201 copolymers), we show that graph construction and self-supervised pretraining are jointly necessary: without pretraining, the large graph method matches the repeat-unit baseline (28.40 K vs. 28.36 K RMSE); with pretraining, it achieves 24.76 K +/- 3.30 K, a 5.1% reduction in mean error over the pretrained repeat-unit baseline (26.08 K +/- 4.20 K, p < 0.001, 30 runs). An ablation removing chemical features degrades performance to 36.65 K, confirming both components are essential. Results are architecture-agnostic, holding for both GINE and GATv2 encoders.

Graph-theoretic approaches offer simplicity, interpretability, and low computational cost for molecular property prediction. Among these, the model proposed by Mukwembi and Nyabadza, based on the external activity $D(G)$ and internal activity $ζ(G)$ indices, achieved strong results on a small flavonoid dataset. However, its ability to generalize to larger and chemically diverse datasets has not been tested. This study evaluates the baseline $D(G)$-$ζ(G)$ polynomial model on five benchmark datasets from MoleculeNet, covering biological activity (BACE, 1,513 molecules), lipophilicity (LogP synthetic, 14,610 molecules; LogP experimental, 753 molecules), aqueous solubility (ESOL, 1,128 molecules), and hydration free energy (SAMPL, 642 molecules). The baseline model achieves an average $R^2 = 0.24$, confirming limited transferability. To address this, a systematic enhancement framework is proposed, progressively incorporating Ridge regularization, additional graph descriptors, physicochemical properties, ensemble learning with Gradient Boosting, Lasso feature selection, and a hybrid approach combining topological indices with Morgan fingerprints. The enhanced models raise the average best $R^2$ to 0.79, with individual improvements ranging from 165% to 274%. All improvements are statistically significant ($p < 0.001$). A direct comparison with a Graph Convolutional Network under identical experimental conditions shows that the enhanced classical models match or outperform deep learning on all five datasets. Comparison with the recent GNN+PGM hybrid of Djagba et al.\ further confirms competitiveness, with the enhanced models achieving the best results on two datasets and tying on one. The entire framework requires no GPU, trains in under five minutes, and uses only open-source tools, making it accessible for researchers in resource-limited settings.