Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?
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- 作者：Jonathan Bisson ; James B. McAlpine ; J. Brent Friesen ; Shao-Nong Chen ; James Graham ; Guido F. Pauli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：59
- 期：5
- 页码：1671-1690
- 全文大小：719K
- 年卷期：Jonathan Bisson
obtained an M.S. degree in structural biochemistry and started his phytochemistry journey under the mentorship of Dr. Vincent Dumontet at the Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France. He then obtained a Ph.D. in Science, Technology and Health from the University of Bordeaux, France, under the mentorship of Dr. Pierre Waffo-Téguo, specializing in methodology at the chemistry–biology interface and practicing liquid–liquid chromatography, NMR spectroscopy, and hyphenated techniques. In 2013, he joined the University of Illinois at Chicago, where he is currently a Postdoctoral Research Associate, developing new methods and IT-based tools for natural products research in interdisciplinary programs, mainly through NMR and chromatographic approaches. Recently, he has been involved in the redesign of the NAPRALERT database.James B. McAlpine
obtained a Ph.D. from the University of New England, Armidale, New South Wales, Australia. Postdoctoral work at Northwestern University Medical School, studying the biosynthesis and mode of action of macrolide antibiotics, followed. In 1972, he joined Abbott Laboratories and worked on macrolides, aminoglycosides, and quinolones before heading up their natural product discovery project from 1981 to 1996; he discovered Tiacumicin B, the API of Difficid. He joined Phytera Inc. as VP Chemistry in 1996, discovering drugs from manipulated plant cell cultures, and in 2002, he joined Ecopia Bio Sciences as VP Chemistry and Discovery using genomics to discover novel secondary metabolites. He has authored or coauthored 120+ papers, is inventor on 50 U.S. patents, and joined UIC as Adjunct Research Professor in 2011.J. Brent Friesen
received his Ph.D. in Natural Products Chemistry from the University of Minnesota, focusing on the biosynthesis of pyridine alkaloids in tobacco. He has spent 10 years in Africa teaching organic chemistry in N’Djamena, Chad, and studying native plants used in Chadian traditional medicines. Currently a Professor of Chemistry at Dominican University, River Forest (IL), he holds an appointment as Adjunct Research Professor at University of Illinois at Chicago. His research encompasses the use of innovative NMR applications in undergraduate laboratories and research as well as the chromatography of bioactive natural products. He has participated in the international countercurrent separation community since 2003 and published articles both independently and in collaboration with the Pauli group at the University of Illinois at Chicago.Shao-Nong Chen
completed a B.S. degree in Organic Chemistry from Lanzhou University, China, as well as an assistantship in the Lanzhou Institute of Chemical Physics (CAS), and then pursued his interests in natural products chemistry, obtaining a Ph.D. under the joint mentorship of Drs. Yao-Zu Chen, Lanzhou University, and Han-Dong Sun, Kunming Institute of Botany (KIB, CAS). After 2 years of postdoctoral training with Dr. Guo-Wei Qin at Shanghai Institute of Materia Medica (SIMM), he joined Dr. Sydney Hecht’s group at the University of Virginia. He moved to UIC in 2000, where he currently is an Assistant Research Professor, working on botanical standardization and integrity in the UIC/NIH Botanical Center, as well as on method development for the analysis of bioactive natural products in interdisciplinary programs.James Graham
received his Ph.D. in Pharmacognosy in 2001, under the tutelage of Dr. Norman Farnsworth at the University of Illinois at Chicago (UIC), conducting ethnobotanical fieldwork in remote areas of Amazonian Peru. He received an NIH postdoctoral Fellowship at Florida International University in the area of Tropical Botanical Medicine. He was also a Technical Officer at the World Health Organization as part of the Traditional Medicine team. Currently, he is a Research Assistant Professor in the Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, at UIC, and has served as editor of the NAPRALERT database since 2011. In addition, he is a Research Associate in Botany at the Field Museum in Chicago, and continues botanical exploration of remote rainforests of Peru.Guido F. Pauli
is a pharmacist by training and holds a doctoral degree in natural products chemistry and pharmacognosy. As Professor and University Scholar at UIC, Chicago (IL), he is principal investigator and collaborator in interdisciplinary natural product-centered research projects as well as director of the NAPRALERT database and the newly formed Center for Natural Products Technologies. His main interests are in the metabolome analysis of complex natural products, bioactive principles, herbal dietary supplements, anti-TB drug discovery, and dental applications of natural agents. Scholarly activities include international collaborations and guest professorships, the education of the next generation of pharmacognosists, and service on funding agency panels, pharmacopoeial expert committees, and in professional societies. His portfolio comprises 150+ peer-reviewed journal articles, international seminars and conference presentations, four book chapters, patents, as well as journal editorial and board functions. - ISSN：1520-4804
文摘
High-throughput biology has contributed a wealth of data on chemicals, including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compounds that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ∼200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence–bioactivity–effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.