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Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.<\/jats:p>","DOI":"10.1007\/s10295-015-1681-y","type":"journal-article","created":{"date-parts":[[2015,9,12]],"date-time":"2015-09-12T05:08:27Z","timestamp":1442034507000},"page":"221-231","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Discovery of novel drug targets and their functions using phenotypic screening of natural products"],"prefix":"10.1093","volume":"43","author":[{"given":"Junghwa","family":"Chang","sequence":"first","affiliation":[{"name":"grid.15444.30 0000000404705454 Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology Yonsei University 120-749 Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Jeong","family":"Kwon","sequence":"additional","affiliation":[{"name":"grid.15444.30 0000000404705454 Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology Yonsei University 120-749 Seoul Republic of Korea"},{"name":"grid.15444.30 0000000404705454 Department of Internal Medicine, College of Medicine Yonsei University 120-752 Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"2023072014375094600_CR1","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1002\/glia.20505","article-title":"N-WASP regulates extension of filopodia and processes by oligodendrocyte progenitors, oligodendrocytes, and Schwann 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