Effective holistic characterization of small molecule effects using heterogeneous biological networks

Frontiers in Pharmacology

Pharmacology

William Mangione¹  Zackary Falls¹  Ram Samudrala² 

[1] Jacobs School of Medicine and Biomedical Sciences, Department of Biomedical Informatics, University at Buffalo, Buffalo, NY, United States;null;

关键词: translational bioinformatics;    systems biology;    drug discovery;    multitargeting;    computational drug repurposing;   

DOI  :  10.3389/fphar.2023.1113007

 received in 2022-11-30, accepted in 2023-04-11,  发布年份 2023

来源: Frontiers

【 摘 要 】

The two most common reasons for attrition in therapeutic clinical trials are efficacy and safety. We integrated heterogeneous data to create a human interactome network to comprehensively describe drug behavior in biological systems, with the goal of accurate therapeutic candidate generation. The Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multiscale therapeutic discovery, repurposing, and design was enhanced by integrating drug side effects, protein pathways, protein-protein interactions, protein-disease associations, and the Gene Ontology, and complemented with its existing drug/compound, protein, and indication libraries. These integrated networks were reduced to a “multiscale interactomic signature” for each compound that describe its functional behavior as vectors of real values. These signatures are then used for relating compounds to each other with the hypothesis that similar signatures yield similar behavior. Our results indicated that there is significant biological information captured within our networks (particularly via side effects) which enhance the performance of our platform, as evaluated by performing all-against-all leave-one-out drug-indication association benchmarking as well as generating novel drug candidates for colon cancer and migraine disorders corroborated via literature search. Further, drug impacts on pathways derived from computed compound-protein interaction scores served as the features for a random forest machine learning model trained to predict drug-indication associations, with applications to mental disorders and cancer metastasis highlighted. This interactomic pipeline highlights the ability of Computational Analysis of Novel Drug Opportunities to accurately relate drugs in a multitarget and multiscale context, particularly for generating putative drug candidates using the information gleaned from indirect data such as side effect profiles and protein pathway information.

【 授权许可】

Unknown   
Copyright © 2023 Mangione, Falls and Samudrala.