Bridging the antiviral drug design gap: a combined machine learning and QSAR approach for drug repurposing of host kinase inhibitors

Vollständiger Abstract

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Abstract Viral outbreaks combined with rapid emergence of mutated viruses have highlighted an urging need for accelerating antiviral drug discovery pipelines. Unfortunately, current drug discovery remains stuck to conventional methods which are slow especially during pandemics. In this article, we present a literature-based synthesis of an integrative machine learning (ML) guided QSAR framework that unifies ligand-based, structure-based, and systems biology approaches towards the aim of generating a host directed antiviral repurposing strategy. Moreover, a modern ML enhanced QSAR modeling strategy is proposed to target host directed therapeutics (HDTs), particularly the host kinase enzymes. The proposed framework integrates molecular descriptor modeling, ensemble learning methods (e.g., RF, gradient boosting), graph neural networks (GNNs), and multi-omics target prioritization to outline a predictive antiviral repurposing model. This structured workflow encompasses dataset assembly, descriptor generation, model training, virtual screening, and experimental validation as sequential stages to guide, rather than as a pipeline that has itself been built or independently validated here, translational deployment. The review is illustrated through a retrospective narrative synthesis of four independently published, clinically relevant repurposed HDTs, namely Baricitinib, Lapatinib, Bemcentinib, and Sunitinib. These published case studies, drawn from the primary literature, exemplify how AI/ML-enhanced QSAR and network-based approaches have been used elsewhere to identify active antiviral kinase inhibitors; they are presented here as illustrative evidence of feasibility of such a computational pipeline. Thus, the AI guided repurposing of host kinase inhibitors offers a systematically accelerated strategy to bridge the drug design gap, with the potential for faster therapeutic deployment against viral threats pending prospective, harmonized validation.