Research Avenues in Drug discovery of natural products
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This document discusses challenges facing the pharmaceutical industry and opportunities for natural products in drug discovery. The pharmaceutical industry faces losses of patent protection for many drugs, increasing costs, and litigation. Natural products are attractive alternatives as they have evolved to be bioactive and have structures not limited by human design. Advances like high-throughput screening, metabolomics, metagenomics, and metabolic engineering can help access natural product diversity and accelerate drug discovery from natural sources.
Research Avenues in Drug discovery of natural products
- 1. Research Advances in the Drug-like Chemical Diversity of Natural ProductsC. DevakumarIndian Council of Agricultural ResearchNew Delhi-110 012adgepd@icar.org.in
- 2. Drug Discovery A process of identifying and optimizing drug candidates consisting of several critical stages:• Program Selection• Target Selection• Assay Development• Lead Generation• Lead Optimization• Identification of a Drug Candidate• Clinical trials
- 4. Pharmaceutical Industry’s Concerns:Eight proprietary drugs with annual worldwide sales of $44 billion in 2007. When they lose patent protection, their sales revenue can drop by 80%. About 25% of the current U.S. drug market will lose patent protection within 4 years. The financial outlook is hampered further by extensive litigation, costs of competitive marketing, and increasing expectations for safety both by the public and by regulatory agencies. All of the easy natural product drug discoveries have been made.The synthesis of natural products is too difficult – the structures are too complex
- 5. Pharmaceutical Industry’s Concerns:Resupply is difficult. Seasonal or environmental variations in the composition can cause problems with initial detection of active compounds as well as subsequent repetition of assays or purification. Loss of source is also possible.Not easily amenable to HTS but Combinatorial chemistry is.Problems of reliable access and supply, especially with respect to higher plants and marine organisms. IPR concerns of local governments and the Rio Convention on Biodiversity.
- 6. THE DEVELOPMENT OF PERSONALIZED MEDICINE—the use of an individual’s DNA sequence as a basis for drug selection. Rapid gene sequencing of individual humans High levels of safety by predicting side effects and assisting the correct choice of therapeutic drugs.New gene-mapping techniques will facilitate speedy diagnostic tests to determine causes of illness, including infections. This could lessen the indiscriminate use of antibiotics and thereby reduce the development of bacterial resistance to such drugs.
- 7. Natural products are attractive for drug discoverySecondary metabolites have evolved to be bioactive.Structures are not limited by the chemist's imagination.The Lipinski rules of five do not apply to natural products.Considering only polyketide metabolites, just over 7000 known structures have led to more than 20 commercial drugs with a “hit rate” of 0.3%, which is much better than the <0.001% hit rate for HTS of synthetic compound libraries.
- 10. Smart ScreeningHTS using differential-sensitivity whole-cell two-plate agar diffusion(the Merck platensimycin assay). The strain expressing antisense RNA to FabH or FabF enzymes of fatty acid biosynthesis is hypersensitive to inhibitors of those proteins. The approach identified two new antibiotics, platensimycinand platencin.
- 11. Cell line AssayMultiple targets are being investigated with the use of cells.An interesting example is single-cell screening of inhibitors of phosphorylation (kinase) signaling pathways using flow cytometry .This makes multiple quantitative measurements of phosphorylation levels of different signaling proteins by measuring specific fluorescently labeled antibodies that recognize them after phosphate attachment.
- 12. RESEARCH ADVANCESAutomated hyphenated techniques with parallel HTS screening library creation accelerates the identification of known compounds and possible hits. Cryoprobes for NMR spectroscopy for enhanced sensitivity with reduced the amount of material required for analysis; for proton spectra, 2 ug of material and carbon correlation spectra on 0.2 mg. Automatically capture substances from HPLC separations by solid-phase extraction and then elute directly into an NMR cryoprobe for analysis.Comparison of NMR signal positions to corresponding databases of known compounds helps in dereplication.
- 13. Pattern matchingOne further approach to identifying or eliminating known natural products without investing resources in their re-isolation and characterization is to compare biological and chemical “fingerprints” with standards. By using the results of multiple biological and chromatographic experiments in which the standard compounds have previously been tested, one can group similar samples together, and pose a dereplication hypothesis for the samples whose results match those of a known compound.
- 14. Future Research AreasWe need to analyse these historical medical formulae and elucidate their synergistic effects.Modern pharmaceutical research, using the powerful tools of genomics, proteomics, metabolomics and synthetic and combinatorial chemistry.
- 15. Future Research AreasIncreasing interest in ‘multi-component therapeutics’ to overcome the challenge of ‘more investment, fewer drugs’Most modern drug discovery has been based on a ‘one-disease– one-target–one-drug’ strategy. The pathogenesis of many diseases involves multiple factors, however, and a selective compound against a single target often fails to achieve the desired effect, particularly in cancer therapy.
- 16. Genomic Overarching of Plants and Humans70% of cancer-related human genes have orthologues in Arabidopsis thaliana (Jones et al, 2008). Some plant secondary metabolites meant to modulate their own metabolism should also be able to bind to molecules that have a role in human disease. For example, multidrug resistance-like proteins are used by Arabidopsis to transport auxin have orthologues in humans that are crucial for the transport of anti-cancer agents; Auxin-distribution modulators such as flavonoids from Arabidopsis can inhibit P-glycoprotein (MDR1) in various human cancer cells (Taylor & Grotewold, 2005).
- 17. Combinatorial BiosynthesisIt resembles assembly lines for making a metabolite by chain elongation and functional group transformation, and can be altered to make new compounds.Combinatorial biosynthesis of analogues of antibiotics, nystatin and andrimid using PKSs and NRPSs was demonstrated.Modular polyketidesynthases (PKSs) and nonribosomal peptide synthetases (NRPSs) are large multidomain enzymes that sequentially condense short fatty acids and a–amino acids, respectively.
- 18. Metabolic EnginneringMany complex natural products from plants can be engineered into heterologous hosts for fermentative production.A well-known example is the effort to produce the antimalarial drug artemisinin in E. coli and yeast. The Keasling group has engineered E. coli to produce its precursor, artemisinic acid, in concentrations of up to 300 mg per liter.
- 19. MetagenomicsIn 1998 the concept of metagenomics was proposed to look at genes and their function in samples obtained directly from the environment . This field has exploded as faster and cheaper gene sequencing is becoming available in combination with the ability to rapidly sort cells from the environment and efficiently clone genes in improved vectors. The metagenomicapproach could afford access to the pool of 99% of unexamined microorganisms.
- 20. MetagenomicsMetagenomics for unculturable organisms: Access to rapid and inexpensive genome sequencing via 454 sequencing or single-molecule real-time (SMRT) methods. It will also uncover “silent pathways” in plants to afford access to a large collection of new products and biocatalysts. It will allow preservation of any threatened species, through cataloging of its genetic blueprint, and may permit recovery of extinct organisms
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