Drug combinations have demonstrated great potential in cancer treatments. They alleviate drug resistance and improve therapeutic efficacy. The fast-growing number of anti-cancer drugs has caused the experimental investigation of all drug combinations to become costly and time-consuming. Computational techniques can improve the efficiency of drug combination screening. Despite recent advances in applying machine learning to synergistic drug combination prediction, several challenges remain. First, the performance of existing methods is suboptimal. There is still much space for improvement. Second, biological knowledge has not been fully incorporated into the model. Finally, many models are lack interpretability, limiting their clinical applications. To address these challenges, we have developed a knowledge-enabled and self-attention transformer boosted deep learning model, TranSynergy, which improves the performance and interpretability of synergistic drug combination prediction. TranSynergy is designed so that the cellular effect of drug actions can be explicitly modeled through cell-line gene dependency, gene-gene interaction, and genome-wide drug-target interaction. A novel Shapley Additive Gene Set Enrichment Analysis (SA-GSEA) method has been developed to deconvolute genes that contribute to the synergistic drug combination and improve model interpretability. Extensive benchmark studies demonstrate that TranSynergy outperforms the state-of-the-art method, suggesting the potential of mechanism-driven machine learning. Novel pathways that are associated with the synergistic combinations are revealed and supported by experimental evidences. They may provide new insights into identifying biomarkers for precision medicine and discovering new anti-cancer therapies. Several new synergistic drug combinations have been predicted with high confidence for ovarian cancer which has few treatment options. The code is available athttps://github.com/qiaoliuhub/drug_combination.

Despite the wealth of single-cell multi-omics data, it remains challenging to predict the consequences of novel genetic and chemical perturbations in the human body. It requires knowledge of molecular interactions at all biological levels, encompassing disease models and humans. Current machine learning methods primarily establish statistical correlations between genotypes and phenotypes but struggle to identify physiologically significant causal factors, limiting their predictive power. Key challenges in predictive modeling include scarcity of labeled data, generalization across different domains, and disentangling causation from correlation. In light of recent advances in multi-omics data integration, we propose a new artificial intelligence (AI)-powered biology-inspired multi-scale modeling framework to tackle these issues. This framework will integrate multi-omics data across biological levels, organism hierarchies, and species to predict genotype-environment-phenotype relationships under various conditions. AI models inspired by biology may identify novel molecular targets, biomarkers, pharmaceutical agents, and personalized medicines for presently unmet medical needs.

Polypharmacology, which focuses on designing therapeutics to target multiple receptors, has emerged as a new paradigm in drug discovery. Polypharmacological effects are an attribute of most, if not all, drug molecules. The efficacy and toxicity of drugs, whether designed as single- or multitarget therapeutics, result from complex interactions between pharmacodynamic, pharmacokinetic, genetic, epigenetic, and environmental factors. Ultimately, to predict a drug response phenotype, it is necessary to understand the change in information flow through cellular networks resulting from dynamic drug-target interactions and the impact that this has on the complete biological system. Although such is a future objective, we review recent progress and challenges in computational techniques that enable the prediction and analysis of in vitro and in vivo drug-response phenotypes.

R47H-TREM2mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.

Advances in next-generation sequencing and high-throughput techniques have enabled the generation of vast amounts of diverse omics data. These big data provide an unprecedented opportunity in biology, but impose great challenges in data integration, data mining, and knowledge discovery due to the complexity, heterogeneity, dynamics, uncertainty, and high-dimensionality inherited in the omics data. Network has been widely used to represent relations between entities in biological system, such as protein-protein interaction, gene regulation, and brain connectivity (i.e. network construction) as well as to infer novel relations given a reconstructed network (aka link prediction). Particularly, heterogeneous multi-layered network (HMLN) has proven successful in integrating diverse biological data for the representation of the hierarchy of biological system. The HMLN provides unparalleled opportunities but imposes new computational challenges on establishing causal genotype-phenotype associations and understanding environmental impact on organisms. In this review, we focus on the recent advances in developing novel computational methods for the inference of novel biological relations from the HMLN. We first discuss the properties of biological HMLN. Then we survey four categories of state-of-the-art methods (matrix factorization, random walk, knowledge graph, and deep learning). Thirdly, we demonstrate their applications to omics data integration and analysis. Finally, we outline strategies for future directions in the development of new HMLN models.