Effective holistic characterization of small molecule effects using heterogeneous biological networks

Abstract

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.

High-throughput label-free opioid receptor binding assays using an automated desorption electrospray ionization mass spectrometry platform

“…Previously established capabilities include the analysis of biosamples for biomarker discovery or large-cohort validation, 35 and the characterization and screening of enzymatic targets. 16,36 We anticipate that these capabilities, together with those for reaction screening (as shown here) and nanoscale synthesis, 37 together with predictive computational tools, 38,39 3 Structures and activity of PZM21 analogues selected from LSF screening campaign. Three functionalized compounds (2-4), see (A) were selected for OR binding assessment and compared against PZM21 (1).…”

“…Previously established capabilities include the analysis of biosamples for biomarker discovery or large-cohort validation, 35 and the characterization and screening of enzymatic targets. 16,36 We anticipate that these capabilities, together with those for reaction screening (as shown here) and nanoscale synthesis, 37 together with predictive computational tools, 38,39 will allow consolidation of the early drug discovery workflow around a single technology.…”