Guiding principles for natural product drug discovery.

Natural products (NPs) have historically been a fertile source of new drugs for the pharmaceutical industry. However, this once-popular approach has waned considerably over the past two decades as the high-throughput screening of megalibraries comprised mainly of molecules with non-natural (synthetic) motifs has unfolded. Contemporary high-throughput screening libraries contain molecules compliant with physicochemical profiles considered essential for downstream development. Until recently, there was no strategy that aligned NP screening with the same physicochemical profiles. An approach based on Log P has addressed these concerns and, together with advances in isolation, afforded NP leads in timelines compatible with pure compound screening. Concomitant progress related to access of biological resources has provided long-awaited legal certainty to further facilitate NP drug discovery.

[1]  B. Munos.  Lessons from 60 years of pharmaceutical innovation , 2009, Nature Reviews Drug Discovery.

[2]  Ricardo Macarron,et al.  Critical review of the role of HTS in drug discovery. , 2006, Drug discovery today.

[3]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[4]  Ronald J. Quinn,et al.  The Identification of Bioactive Natural Products by High Throughput Screening (HTS) , 2010 .

[5]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[6]  F. Koehn,et al.  The evolving role of natural products in drug discovery , 2005, Nature Reviews Drug Discovery.

[7]  D. Bojanic,et al.  Impact of high-throughput screening in biomedical research , 2011, Nature Reviews Drug Discovery.

[8]  L. Mander,et al.  Comprehensive Natural Products II: Chemistry and Biology , 2010 .

[9]  Fiona McConnell,et al.  The Biodiversity Convention: A Negotiating History. , 1997, American Journal of International Law.

[10]  K U. Bindseil,et al.  Pure compound libraries; a new perspective for natural product based drug discovery. , 2001, Drug discovery today.

[11]  V. Avery,et al.  (+)-7-Bromotrypargine: an antimalarial β-carboline from the Australian marine sponge Ancorina sp. , 2010 .

[12]  Melissa Sykes,et al.  Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa. , 2011, Bioorganic & medicinal chemistry.

[13]  E. Evans-Illidge,et al.  Marine natural products discovery in Australia: From reef to royalty, and the pursuit of Convention for Biological Diversity (CBD) compliance , 2007 .

[14]  A. Ganesan.  The impact of natural products upon modern drug discovery. , 2008, Current opinion in chemical biology.

[15]  D. Janzen,et al.  An intellectual property rights framework for biodiversity prospecting. , 1993 .

[16]  B. Shoichet.  Screening in a spirit haunted world. , 2006, Drug discovery today.

[17]  Brian K. Shoichet,et al.  Virtual Screening in Drug Discovery , 2005 .

[18]  G. Rishton,et al.  Molecular diversity in the context of leadlikeness: compound properties that enable effective biochemical screening. , 2008, Current opinion in chemical biology.

[19]  Santiago Carrizosa.  Accessing biodiversity and sharing the benefits : lessons from implementing the convention on biological diversity , 2004 .

[20]  V. Avery,et al.  Antimalarial benzylisoquinoline alkaloid from the rainforest tree Doryphora sassafras. , 2009, Journal of natural products.

[21]  Matthias Buck,et al.  The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization to the Convention on Biological Diversity , 2011 .

[22]  A. Harvey,et al.  Medicines from nature: are natural products still relevant to drug discovery? , 1999, Trends in pharmacological sciences.

[23]  A. Carroll,et al.  Endiandrin A, a potent glucocorticoid receptor binder isolated from the Australian plant Endiandra anthropophagorum. , 2007, Journal of natural products.

[24]  Sanjivanjit K. Bhal,et al.  The Rule of Five revisited: applying log D in place of log P in drug-likeness filters. , 2007, Molecular pharmaceutics.

[25]  J. Baell.  Observations on screening-based research and some concerning trends in the literature. , 2010, Future medicinal chemistry.

[26]  A Srinivas Reddy,et al.  Virtual screening in drug discovery -- a computational perspective. , 2007, Current protein & peptide science.

[27]  A. Gorse.  Diversity in medicinal chemistry space. , 2006, Current topics in medicinal chemistry.

[28]  Ian Paterson,et al.  Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C7-24 and Finale , 2004 .

[29]  C. Dobson.  Chemical space and biology , 2004, Nature.

[30]  John Steele,et al.  Drug-like properties: guiding principles for design - or chemical prejudice? , 2004, Drug discovery today. Technologies.

[31]  V. Avery,et al.  Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp. , 2011, Organic & biomolecular chemistry.

[32]  V. Avery,et al.  Antimalarial bromotyrosine derivatives from the Australian marine sponge Hyattella sp. , 2010, Journal of natural products.

[33]  Alejandro Grajal.  Biodiversity and the Nation State: Regulating Access to Genetic Resources Limits Biodiversity Research in Developing Countries , 1999 .

[34]  J. Gasteiger,et al.  COMDECOM: Predicting the Lifetime of Screening Compounds in DMSO Solution , 2009, Journal of biomolecular screening.

[35]  Ronald J. Quinn,et al.  Biodiscovery for Natural Product Pharmaceuticals: An Australian Experience , 2007 .

[36]  George G Harrigan,et al.  Chemical and biological integrity in natural products screening. , 2005, Combinatorial chemistry & high throughput screening.

[37]  M. Elofsson,et al.  Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges. , 2012, Organic & biomolecular chemistry.

[38]  Rohan A Davis,et al.  Antimalarial activity of azafluorenone alkaloids from the Australian tree Mitrephora diversifolia. , 2009, Journal of natural products.

[39]  M. Auer.  Access to genetic resources and benefit sharing , 2001 .

[40]  F. Vivien,et al.  The convention on biological diversity: A conventionalist approach , 2005 .

[41]  Tudor I. Oprea,et al.  4 Compound Selection for Virtual Screening , 2005 .

[42]  A. Hofmann,et al.  Merging structural biology with chemical biology: Structural Chemistry at Eskitis , 2010 .

[43]  M. O'Neil-Johnson,et al.  High-throughput method for the production and analysis of large natural product libraries for drug discovery. , 2002, Analytical chemistry.

[44]  Principles and practice of Hansch analysis: a guide to structure-activity correlation for the medicinal chemist. , 1971, Advances in drug research.

[45]  C. Díaz,et al.  Characterization of binary solvent mixtures of DMSO with water and other cosolvents. , 2001, The Journal of organic chemistry.

[46]  D. Pereira,et al.  Origin and evolution of high throughput screening , 2007, British journal of pharmacology.

[47]  Melissa M. Wagenaar,et al.  Pre-fractionated Microbial Samples – The Second Generation Natural Products Library at Wyeth , 2008, Molecules.

[48]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[49]  C. Hansch.  Quantitative approach to biochemical structure-activity relationships , 1969 .

[50]  V. Avery,et al.  Antitrypanosomal cyclic polyketide peroxides from the Australian marine sponge Plakortis sp. , 2010, Journal of natural products.

[51]  Lars Bohlin,et al.  Bioassay methods in natural product research and drug development : proceedings of the international symposium on Bioassay Methods in Natural Product Research and Drug Development, held at the Biomedical Centre of Uppsala University, Sweden, from 24-27 August 1997 , 1999 .

[52]  T. Ramsey,et al.  Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 2: Synthesis of Fragments C1-6 and C9-14 , 2004 .

[53]  Sorel Muresan,et al.  Developing a drug-like natural product library. , 2008, Journal of natural products.

[54]  Tute Ms.  Principles and practice of Hansch analysis: a guide to structure-activity correlation for the medicinal chemist. , 1971 .

[55]  Vicky Avery,et al.  Progress toward establishing an open access molecular screening capability in the Australasian region. , 2007, ACS chemical biology.

[56]  L. Llewellyn,et al.  A Tropical Marine Microbial Natural Products Geobibliography as an Example of Desktop Exploration of Current Research Using Web Visualisation Tools , 2008, Marine drugs.

[57]  Joshua A. Kritzer,et al.  Grand challenge commentary: Beyond discovery: probes that see, grab and poke. , 2010, Nature chemical biology.

[58]  Rohan A Davis,et al.  Drug-like properties: guiding principles for the design of natural product libraries. , 2012, Journal of natural products.

[59]  F. Lombardo,et al.  ElogPoct: a tool for lipophilicity determination in drug discovery. , 2000, Journal of medicinal chemistry.

[60]  F. de la Calle,et al.  Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B. , 2000, Organic letters.

[61]  S. Xue,et al.  Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide. Part 1: Synthetic strategy and preparation of a common precursor , 2004 .

[62]  R. Dalton.  Natural resources: Bioprospects less than golden , 2004, Nature.

[63]  G A Petsko,et al.  Chemistry and biology. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  A. Harvey,et al.  Strategies for discovering drugs from previously unexplored natural products. , 2000, Drug discovery today.

[65]  David R. Appleton,et al.  A simple method for high-throughput extract prefractionation for biological screening , 2007 .

[66]  Kyria Boundy-Mills,et al.  Natural product libraries to accelerate the high-throughput discovery of therapeutic leads. , 2011, Journal of natural products.

[67]  Sandra L. Nelson,et al.  The Effect of Freeze/Thaw Cycles on the Stability of Compounds in DMSO , 2003, Journal of biomolecular screening.

[68]  T. Ramsey,et al.  Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 4: Preparation of Fragment C7-24 , 2004 .

[69]  Ronald J. Quinn,et al.  High‐throughput screening in natural product drug discovery in Australia utilising Australia's biodiversity , 1999 .

[70]  J. DiMasi,et al.  The cost of biopharmaceutical R&D: is biotech different? , 2007 .

[71]  Lyle Glowka,et al.  A guide to designing legal frameworks to determine access to genetic resources , 1998 .

[72]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[73]  Tudor I. Oprea,et al.  Pursuing the leadlikeness concept in pharmaceutical research. , 2004, Current opinion in chemical biology.

[74]  V. Avery,et al.  Pseudoceratinazole A: a novel bromotyrosine alkaloid from the Australian sponge Pseudoceratina sp , 2010 .

[75]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[76]  A. Carroll,et al.  (-)-Dibromophakellin: an alpha2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata. , 2009, Bioorganic & medicinal chemistry.

[77]  James Inglese,et al.  Apparent activity in high-throughput screening: origins of compound-dependent assay interference. , 2010, Current opinion in chemical biology.

[78]  Ronald J. Quinn,et al.  QPRI’s System for Screening of Natural Products , 1999 .

[79]  Elizabeth Evans-Illidge,et al.  Natural Ways: Learning from Nature's 4.5 Billion Year Biotechnology Project , 2004 .

[80]  P. Crews,et al.  A selective account of effective paradigms and significant outcomes in the discovery of inspirational marine natural products. , 2009, Journal of natural products.

[81]  Mark T. D. Cronin,et al.  The Role of Hydrophobicity in Toxicity Prediction , 2006 .

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

[83]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[84]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[85]  Li Di,et al.  Coexistence of passive and carrier-mediated processes in drug transport , 2010, Nature Reviews Drug Discovery.

[86]  R. Frank,et al.  New estimates of drug development costs. , 2003, Journal of health economics.

[87]  Han van de Waterbeemd,et al.  Property-Based Design: Optimization of Drug Absorption and Pharmacokinetics , 2001 .

[88]  Jonathan Kennedy,et al.  Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. , 2008, Natural product reports.

[89]  M. Hann.  Molecular obesity, potency and other addictions in drug discovery , 2011 .

[90]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[91]  Paul D Leeson,et al.  Time-related differences in the physical property profiles of oral drugs. , 2004, Journal of medicinal chemistry.

[92]  Ricardo Macarrón,et al.  Yin and Yang in medicinal chemistry: what does drug-likeness mean? , 2011, Future medicinal chemistry.

[93]  J. White.  The Commercial Use of Biodiversity: Access to Genetic Resources and Benefit-sharing , 2001 .

[94]  F. Hirayama,et al.  Safracins, new antitumor antibiotics. I. Producing organism, fermentation and isolation. , 1983, The Journal of antibiotics.

[95]  M. K. Harper,et al.  Marine Natural Product Libraries for High-Throughput Screening and Rapid Drug Discovery , 2008, Journal of natural products.

[96]  U. Abel,et al.  Modern methods to produce natural-product libraries. , 2002, Current opinion in chemical biology.

[97]  Alan L Harvey,et al.  Natural products as a screening resource. , 2007, Current opinion in chemical biology.

[98]  G. Cordell,et al.  Natural products and traditional medicine: turning on a paradigm. , 2012, Journal of natural products.

[99]  Kip Guy,et al.  Automated high-throughput system to fractionate plant natural products for drug discovery. , 2010, Journal of natural products.