Direct and indirect approaches to identify drug modes of action.
Phenotypic assays are becoming increasingly more common among drug discovery practices, expanding drug target diversity as lead compounds identified through such screens are not limited to known targets. While increasing diversity is beneficial to the drug discovery process and the fight against disease, the unknown modes of action of new lead compounds can hamper drug discovery as, in most cases, the process of lead compound optimization is made difficult due to the unknown nature of the target; blindly changing substituents can prove fruitless due to the inexhaustible number of potential combinations, and it is therefore desirable to rapidly identify the targets of lead compounds developed through phenotypic screening. In addition, leads identified through target-based screening often have off-target effects that contribute towards drug toxicity, and by identifying those secondary targets, the drugs can be improved. However, the identification of a leads mode of action is far from trivial and now represents a major bottleneck in the drug discovery pipeline. This review looks at some of the recent developments in the identification of drug modes of action, focusing on phenotype-based methods using metabolomics, proteomics, transcriptomics, and genomics to detect changes in phenotype in response to the presence of the drug, and affinity-based methods using modified/unmodified drug as bait to capture and identify targets. © 2017 IUBMB Life, 70(1):9-22, 2018.
['Tulloch|Lindsay B|LB|', 'Menzies|Stefanie K|SK|', 'Coron|Ross P|RP|', 'Roberts|Matthew D|MD|', 'Florence|Gordon J|GJ|', 'Smith|Terry K|TK|0000-0003-1994-2009']
D002853:Chromatography, Liquid D015195:Drug Design D055808:Drug Discovery D023281:Genomics D057166:High-Throughput Screening Assays D006801:Humans D055432:Metabolomics D058990:Molecular Targeted Therapy D011485:Protein Binding D020543:Proteome D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization D053719:Tandem Mass Spectrometry
drug mode of action metabolomics proteomics transcriptomics genomics affinity chromatography photo-affinity labeling target ID