Parameter-Efficient Computational Drug Discovery using Deep Learning

The accurate prediction of small molecule binding affinity and toxicity remains a central challenge in drug discovery, with significant implications for reducing development costs, improving candidate prioritization, and enhancing safety profiles. Traditional computational approaches, such as molecular docking and quantitative structure-activity relationship (QSAR) models, often rely on handcrafted features and require extensive domain knowledge, which can limit scalability and generalization to novel chemical scaffolds. Recent advances in language models (LMs), particularly those adapted to chemical representations such as SMILES (Simplified Molecular Input Line Entry System), have opened new ways for learning data-driven molecular representations that capture complex structural and functional properties. However, achieving both high binding affinity and low toxicity through a resource-efficient computational pipeline is inherently difficult due to the multi-objective nature of the task. This study presents a novel dual-paradigm approach to critical challenges in drug discovery: predicting small molecules with high binding affinity and low cardiotoxicity profiles. For binding affinity prediction, we implement a specialized graph neural network (GNN) architecture that operates directly on molecular structures represented as graphs, where atoms serve as nodes and bonds as edges. This topology-aware approach enables the model to capture complex spatial arrangements and electronic interactions critical for protein-ligand binding. For toxicity prediction, we leverage chemical language models (CLMs) fine-tuned with Low-Rank Adaptation (LoRA), allowing efficient adaptation of large pre-trained models to specialized toxicological endpoints while maintaining the generalized chemical knowledge embedded in the base model. Our hybrid methodology demonstrates significant improvements over existing computational approaches, with the GNN component achieving an average area under the ROC curve (AUROC) of 0.92 on three protein targets and the LoRA-adapted CLM reaching (AUROC) of 0.90 with 60% reduction in parameter usage in predicting cardiotoxicity. This work establishes a powerful computational framework that accelerates drug discovery by enabling both higher binding affinity and low toxicity compounds with optimized efficacy and safety profiles.