The polypharmacology of natural products.

The once-popular approach of using natural products as a prime source for medicinal chemistry and drug discovery has waned considerably in the past two decades due to the advent of high-throughput screening of small molecule mega libraries. However, the growing appreciation of network pharmacology as the next drug-discovery paradigm suggests that natural products and their unique polypharmacology offer significant advantages for finding novel therapeutics particularly for the treatment of complex and multifactorial diseases. Drug discovery process is awaiting the revitalization of interest in natural products and their derivatives. The current challenge is how to decipher this natural chemical diversity.

[1]  Liang Shen,et al.  Berberine: A Potential Multipotent Natural Product to Combat Alzheimer’s Disease , 2011, Molecules.

[2]  Herbert Waldmann,et al.  Protein structure similarity clustering (PSSC) and natural product structure as inspiration sources for drug development and chemical genomics. , 2005, Current opinion in chemical biology.

[3]  Stefan Wetzel,et al.  Charting, navigating, and populating natural product chemical space for drug discovery. , 2012, Journal of medicinal chemistry.

[4]  O. Werz,et al.  Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1 , 2009, Molecular Cancer Therapeutics.

[5]  Y. Silla,et al.  Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics. , 2017, Molecular bioSystems.

[6]  A. Azmi Network pharmacology for cancer drug discovery: are we there yet? , 2012, Future medicinal chemistry.

[7]  Jayme L. Dahlin,et al.  The Essential Medicinal Chemistry of Curcumin , 2017, Journal of medicinal chemistry.

[8]  B. Aggarwal,et al.  Curcumin as "Curecumin": from kitchen to clinic. , 2008, Biochemical pharmacology.

[9]  Bin Liu,et al.  Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum , 2015, Nature Communications.

[10]  Herbert Waldmann,et al.  From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. , 2002, Angewandte Chemie.

[11]  D. Gilroy,et al.  15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation , 2004, The Journal of experimental medicine.

[12]  M. Nguyen,et al.  Catechol‐Based Ligands as Potential Metal Chelators Inhibiting Redox Activity in Alzheimer's Disease , 2017 .

[13]  S. Pervaiz,et al.  Pro‐oxidant Activity of Low Doses of Resveratrol Inhibits Hydrogen Peroxide—Induced Apoptosis , 2003, Annals of the New York Academy of Sciences.

[14]  K. Block,et al.  Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy , 2006, Integrative cancer therapies.

[15]  D. Newman,et al.  Natural Products as Sources of New Drugs from 1981 to 2014. , 2016, Journal of natural products.

[16]  S. Baron,et al.  Distribution of trans-resveratrol and its metabolites after acute or sustained administration in mouse heart, brain, and liver. , 2017, Molecular nutrition & food research.

[17]  H. Waldmann,et al.  Natural products are biologically validated starting points in structural space for compound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitors. , 2002, Angewandte Chemie.

[18]  D. K. Arrell,et al.  Network Systems Biology for Drug Discovery , 2010, Clinical pharmacology and therapeutics.

[19]  Y. Siow,et al.  Redox regulation in health and disease — Therapeutic potential of berberine , 2011 .

[20]  M. Portillo,et al.  Resveratrol Metabolites Modify Adipokine Expression and Secretion in 3T3-L1 Pre-Adipocytes and Mature Adipocytes , 2013, PloS one.

[21]  Y. Touitou,et al.  Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night , 2009, Redox report : communications in free radical research.

[22]  Jürgen Bajorath,et al.  Determining the Degree of Promiscuity of Extensively Assayed Compounds , 2016, PloS one.

[23]  W. Cho,et al.  Pharmacological effects of berberine and its derivatives: a patent update , 2016, Expert opinion on therapeutic patents.

[24]  D. K. Agrawal,et al.  Curcumin and its analogues: Potential anticancer agents , 2009, Medicinal research reviews.

[25]  C. Glorieux,et al.  Redox-active quinones and ascorbate: an innovative cancer therapy that exploits the vulnerability of cancer cells to oxidative stress. , 2011, Anti-cancer agents in medicinal chemistry.

[26]  Aamir Ahmad,et al.  A prooxidant mechanism for the anticancer and chemopreventive properties of plant polyphenols. , 2012, Current drug targets.

[27]  R. Iyengar,et al.  Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. , 2012, Annual review of pharmacology and toxicology.

[28]  David R Bickers,et al.  Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. , 2009, Archives of biochemistry and biophysics.

[29]  S. Redenti,et al.  Digitoxin enhances the growth inhibitory effects of thapsigargin and simvastatin on ER negative human breast cancer cells. , 2016, Fitoterapia.

[30]  B. Aggarwal,et al.  Resveratrol: A multitargeted agent for age-associated chronic diseases , 2008, Cell cycle.

[31]  A. Tsatsakis,et al.  Resveratrol as MDR reversion molecule in breast cancer: An overview. , 2017, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[32]  Robert A Newman,et al.  Bioavailability of curcumin: problems and promises. , 2007, Molecular pharmaceutics.

[33]  Oliver Werz,et al.  Multi-target approach for natural products in inflammation. , 2014, Drug discovery today.

[34]  Lirong Chen,et al.  Use of Natural Products as Chemical Library for Drug Discovery and Network Pharmacology , 2013, PloS one.

[35]  Ronald J Quinn,et al.  Identification of Protein Fold Topology Shared between Different Folds Inhibited by Natural Products , 2007, Chembiochem : a European journal of chemical biology.

[36]  B. Aggarwal,et al.  Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. , 2008, Cancer letters.

[37]  A. Schuffenhauer,et al.  Charting biologically relevant chemical space: a structural classification of natural products (SCONP). , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. K. Kundu,et al.  Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. , 2008, Cancer letters.

[39]  A. Roda,et al.  Berberine: New Insights from Pharmacological Aspects to Clinical Evidences in the Management of Metabolic Disorders. , 2016, Current medicinal chemistry.

[40]  B. Kemp,et al.  The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase , 2012, Science.

[41]  A. Scovassi,et al.  Berberine: new perspectives for old remedies. , 2012, Biochemical pharmacology.

[42]  U. Förstermann,et al.  Antioxidant effects of resveratrol in the cardiovascular system , 2017, British journal of pharmacology.

[43]  J. Golenser,et al.  Current perspectives on the mechanism of action of artemisinins. , 2006, International journal for parasitology.

[44]  K. Becker,et al.  Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. , 2004, International journal for parasitology.

[45]  S. Pongor,et al.  Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[46]  H. Ahsan,et al.  Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. , 1999, Chemico-biological interactions.

[47]  P. Olliaro,et al.  Possible modes of action of the artemisinin-type compounds. , 2001, Trends in parasitology.

[48]  N. Braidy,et al.  Resveratrol and Alzheimer’s Disease: Mechanistic Insights , 2017, Molecular Neurobiology.

[49]  Christina L. L. Chai,et al.  Metabolism‐Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development , 2016, ChemMedChem.

[50]  Jacob,et al.  Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID‐enteropathy in the rat , 2000, Alimentary pharmacology & therapeutics.

[51]  Sahdeo Prasad,et al.  Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases , 2017, British journal of pharmacology.

[52]  G. Padmanaban,et al.  Curcumin May Defy Medicinal Chemists. , 2017, ACS medicinal chemistry letters.

[53]  V. Barton,et al.  The Molecular Mechanism of Action of Artemisinin—The Debate Continues , 2010, Molecules.

[54]  I. Villegas,et al.  Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. , 2007, Biochemical Society transactions.

[55]  X. Su,et al.  Discovery, mechanisms of action and combination therapy of artemisinin , 2009, Expert review of anti-infective therapy.

[56]  A. Bishayee Cancer Prevention and Treatment with Resveratrol: From Rodent Studies to Clinical Trials , 2009, Cancer Prevention Research.

[57]  J. Ferrières The French paradox: lessons for other countries , 2003, Heart.

[58]  P. B. Luis,et al.  Degradation of Curcumin: From Mechanism to Biological Implications. , 2015, Journal of agricultural and food chemistry.

[59]  B. Aggarwal,et al.  Curcumin and cancer: an "old-age" disease with an "age-old" solution. , 2008, Cancer letters.

[60]  Chuang Liu,et al.  In silico polypharmacology of natural products , 2017, Briefings Bioinform..

[61]  Alan L Harvey,et al.  Natural products in drug discovery. , 2008, Drug discovery today.

[62]  Herbert Waldmann,et al.  Natural product guided compound library development. , 2002, Current medicinal chemistry.

[63]  Herbert Waldmann,et al.  Protein Structure Similarity as Guiding Principle for Combinatorial Library Design , 2003, Biological chemistry.

[64]  H. Hausenblas,et al.  Resveratrol and health--a comprehensive review of human clinical trials. , 2011, Molecular nutrition & food research.

[65]  J. J. Moreno,et al.  Resveratrol metabolites have an antiproliferative effect on intestinal epithelial cancer cells. , 2012, Food chemistry.

[66]  A. Banerjee,et al.  Concentration dependent antioxidant/pro-oxidant activity of curcumin studies from AAPH induced hemolysis of RBCs. , 2008, Chemico-biological interactions.

[67]  Wei-Jia Kong,et al.  Learning from berberine: Treating chronic diseases through multiple targets , 2015, Science China Life Sciences.

[68]  R. Russell,et al.  Illuminating drug discovery with biological pathways , 2005, FEBS letters.

[69]  J. Le Bail,et al.  Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol. , 2000, Life sciences.