Elucidation of specific binding of drugs with the nucleic acid to control important cellular functions has been an active area of research since several years. The impetus underlying for studying drug-nucleic acid interactions is the desire to know the molecular mechanism of drug action.
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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.
Modern chemical biology and drug discovery each seek to identify new small molecules that potently and selectively modulate the functions of target proteins. Historically, nature has been an important source for such molecules, with knowledge of toxic or medicinal properties often long predating knowledge of precise target or mechanism. Natural selection provides a slow and steady stream of bioactive small molecules, but each of these molecules must perforce confer reproductive advantage in order for nature to ‘invest’ in its synthesis. In recent decades, investments in finding new small-molecule probes and drugs have expanded to a paradigm of screening large numbers (typically 103–106) of compounds for those that elicit a desired biological response n some cases, these studies interrogate natural products but more often they involve collections of synthetic small molecules prepared by organic chemistry strategiesthat rapidly yield large collections of relatively pure compounds. Thus, the overall discovery paradigm involves investments both in organic synthesis and in biological testing of large compound collections.
Since the revolution in molecular biology, the biological testing component of screening-based discovery has overwhelmingly involved testing compounds for effects on purified proteins. However, with advances in assay technology, many research programs are increasingly turning (or returning) to cell- or organism- based phenotypic assays that benefit from preserving the cellular context of protein function The cost paid for this benefit is that the precise protein targets or mechanisms of action responsible for the observed phenotypes remain to be determined. Even after a relevant target is established, additional functional studies may help to identify unwanted off-target effects or establish new roles for the target protein in biological networks. In this review, we address these important steps in the discovery process, termed target identification or deconvolution illustrating methods available to approach the problem, highlighting recent advances and discussing how findings from multiple approaches are integrated.
Modern chemical biology and drug discovery each seek to identify new small molecules that potently and selectively modulate the functions of target proteins. Historically, nature has been an important source for such molecules, with knowledge of toxic or medicinal properties often long predating knowledge of precise target or mechanism. Natural selection provides a slow and steady stream of bioactive small molecules, but each of these molecules must perforce confer reproductive advantage in order for nature to ‘invest’ in its synthesis. In recent decades, investments in finding new small-molecule probes and drugs have expanded to a paradigm of screening large numbers (typically 103–106) of compounds for those that elicit a desired biological response n some cases, these studies interrogate natural products but more often they involve collections of synthetic small molecules prepared by organic chemistry strategiesthat rapidly yield large collections of relatively pure compounds. Thus, the overall discovery paradigm involves investments both in organic synthesis and in biological testing of large compound collections.
Since the revolution in molecular biology, the biological testing component of screening-based discovery has overwhelmingly involved testing compounds for effects on purified proteins. However, with advances in assay technology, many research programs are increasingly turning (or returning) to cell- or organism- based phenotypic assays that benefit from preserving the cellular context of protein function The cost paid for this benefit is that the precise protein targets or mechanisms of action responsible for the observed phenotypes remain to be determined. Even after a relevant target is established, additional functional studies may help to identify unwanted off-target effects or establish new roles for the target protein in biological networks. In this review, we address these important steps in the discovery process, termed target identification or deconvolution illustrating methods available to approach the problem, highlighting recent advances and discussing how findings from multiple approaches are integrated.
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