Target identification and mechanism of action in chemical biology and drug discovery

Abstract

Target-identification and mechanism-of-action studies have important roles in small-molecule probe and drug discovery. Biological and technological advances have resulted in the increasing use of cell-based assays to discover new biologically active small molecules. Such studies allow small-molecule action to be tested in a more disease-relevant setting at the outset, but they require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of small-molecule action.

A review of connectivity map and computational approaches in pharmacogenomics

“…Such data types are now routinely used to aid our understanding in drug discovery and disease therapeutics [1,2]. With the rapid accumulation of genomics and chemical informatics data in the past decade, several new systematic approaches to drug discovery have been proposed.…”

The re-emergence of natural products for drug discovery in the genomics era

“…With the development of high-content screening and other phenotypic assays that use cells or model organisms 19,20 , test-compound bioavailability becomes important earlier in the screening cascade than if the primary assay is a molecular one, such as an isolated protein assay. There is also increasing interest in the clues from traditional uses of plant extracts for example, those in Chinese traditional medicine to guide new drug discovery.…”

Discovery and resupply of pharmacologically active plant-derived natural products: A review

“…However, this terminology use is conflicting with the mainstream understanding existing in the broad drug discovery scientific community, which would see the "bedside-to-bench" strategy as a classical forward pharmacology (phenotypic drug discovery) example starting with observation of phenotypic changes at organismal level [e.g., reversal of disease symptoms in patients; Schenone et al, 2013;Takenaka, 2001;Zheng et al, 2013)]. In this sense, terminology standardization is needed in order to avoid miscommunication between researchers from different scientific disciplines.…”

“…Both the forward and the reverse pharmacology approaches use an overlapping selection of bioassays but differ in the stage when the assays are applied ( Fig. 3; Schenone et al, 2013;Takenaka, 2001;Zheng et al, 2013)). …”