A novel approach for target deconvolution from phenotype-based screening using knowledge graph.

Deconvoluting drug targets is crucial in modern drug development, yet both traditional and artificial intelligence (AI)-driven methods face challenges in terms of completeness, accuracy, and efficiency. Identifying drug targets, especially within complex systems such as the p53 pathway, remains a formidable task. The regulation of this pathway by myriad stress signals and regulatory elements adds layers of complexity to the discovery of effective p53 pathway activators. Recent insights into p53 activation have led to two main screening strategies for p53 activators. The target-based approach focuses on p53 and its regulators (MDM2, MDMX, USP7, Sirt proteins), but requires separate systems for each target and may miss multi-target compounds. Phenotype-based screening can reveal new targets but involves a lengthy process to elucidate mechanisms and targets, hindering drug development. Knowledge graphs have emerged as powerful tools that offer strengths in link prediction and knowledge inference to address these issues. In this study, we constructed a protein-protein interaction knowledge graph (PPIKG) and pioneered an integrated drug target deconvolution system that combines AI with molecular docking techniques. Analysis based on the PPIKG narrowed down candidate proteins from 1088 to 35, significantly saving time and cost. Subsequent molecular docking led us to pinpoint USP7 as a direct target for the p53 pathway activator UNBS5162. Leveraging knowledge graphs and a multidisciplinary approach allows us to streamline the laborious and expensive process of reverse targeting drug discovery through phenotype screening. Our findings have the potential to revolutionize drug screening and open new avenues in pharmacological research, increasing the speed and efficiency of pursuing novel therapeutics. The code is available at  https://github.com/Xiong-Jing/PPIKG .