File Name: natural products in drug discovery and development .zip
Box V, Melbourne, Victoria , Australia. Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered.
In the fields of medicine , biotechnology and pharmacology , drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules , natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology.
Ayurveda and natural products drug discovery. IntroductionNatural products, including plants, animals and minerals have been the basis of treatment of human diseases. History of medicine dates back practically to the existence of human civilization. The current accepted modern medicine or allopathy has gradually developed over the years by scientific and observational efforts of scientists.
However, the basis of its development remains rooted in traditional medicine and therapies. The history of medicine includes many ludicrous therapies. Nevertheless, ancient wisdom has been the basis of modern medicine and will remain as one important source of future medicine and therapeutics. The future of natural products drug discovery will be more holistic, personalized and involve wise use of ancient and modern therapeutic skills in a complementary manner so that maximum benefits can be accrued to the patients and the community 1.
The Greek physician Galen AD devised the first pharmacopoeia describing the appearance, properties and use of many plants of his time.
The foundations of the modern pharmaceutical industry were laid when techniques were developed to produce synthetic replacements for many of the medicines that had been derived from the forest.
Natural products chemistry actually began with the work of Serturner, who first isolated morphine from opium. This, in turn, was obtained from opium poppy Papaver somniferum by processes that have been used for over years. Many such similar developments followed.
Quinine from cinchona tree had its origin in the royal households of the South American Incas. Before the first European explorers arrived, the native people of the Americas had developed complex medical systems replete with diagnosis and treatment of physical as well as spiritual illnesses.
Indigenous peoples derived medicines and poisons from thousands of plants. A review of some plants that originated from Central and South America indicates that most of them either had potentially toxic characters or were from food sources. The following are a few examples 2 : In the early s, Indian fever bark was one of the first medicinal plants to find appreciative consumers in Europe. Taken from the cinchona tree Cinchona officinalis , the bark was used as an infusion by native people of the Andes and Amazon highlands to treat fevers.
Jesuit missionaries brought the bark back to Europe. By the early sixteenth century, this medicine was known as 'Jesuit fever bark', quite a transformation. The name coca Erythroxylum coca comes from an Aymara word meaning 'tree'. In Andean cultures, the leaves of the coca tree have been primarily chewed to obtain perceived benefits. From ancient times, indigenous people have added alkaline materials such as crushed seashells or burnt plant ashes to the leaves in order to accentuate the pharmacologically active moiety of coca.
In , a German chemist Carl Koler isolated cocaine, the chemical responsible for the biological activity. He found that cocaine could act as a local anaesthetic in eye surgery. As the years passed, scientists observed that cocaine paralyzed nerve endings responsible for transmitting pain. As a local anaesthetic, it revolutionized several surgical and dental procedures.
Pot curare arrowhead poison used in the East Amazon is predominately from the species Strychnos guianensis. Tube curare in the West Amazon is from Chrondrodendron tomentosum; curare in modern medicine is made from this and named as tubocurarine. The jaborandi tree Pilocarpus jaborandi secretes alkaloid-rich oil. Several substances are extracted from this aromatic oil, including the alkaloid pilocarpine, a weapon against the blinding disease, glaucoma.
American Indians on the island of Guadeloupe used pineapple Ananas comosos poultices to reduce inflammation in wounds and other skin injuries, to aid digestion and to cure stomachache. In , an enzyme that broke down proteins bromelain was isolated from the fresh juice of pineapple and was found to break down blood clots.
Other pharmaceuticals that have their origin in botanicals include atropine, hyoscine, digoxin, colchicine and emetine. Reserpine, an anti-hypertensive alkaloid Rauwolfia serpentina became available as a result of work carried out by Ciba-Geigy in India. It is pertinent to note that most of these early discoveries are mainly based on traditional medicines; many products could act as poisons in toxic doses.
Discovering medicines or poisons? A major problem with traditional, indigenous medicine is discovering a reliable 'living tradition' rather than relying upon second-hand accounts of their value and use. In many parts of the world the indigenous systems of medicine have almost completely broken down and disappeared.
This includes mostly developed countries and some developing countries where the indigenous population has been marginalized. In others, the system is fragmented with the use of indigenous materials being limited to small tribal and geographical areas, as in many parts of Africa.
In anthropological terms these are 'little traditions', while the Ayurvedic Indian and traditional Chinese systems are living 'great traditions'.
Although the little traditions are an excellent repository of knowledge about medicinal and poisonous properties of botanicals, researchers have mainly exploited poisonous sources. This may be primarily because of many reasons.
First, it is relatively easy to present and demonstrate poisonous characteristics of botanicals. Second, there may not be a written documentation and poisonous characters get predominance by word of mouth. Third, for an outsider, poisonous characteristics differentiate between ordinary and extraordinary material for pharmaceutical development. Fourth, a considerable time period is required to demonstrate true medicinal activities with proven safety profile. Great traditions have relatively organized database, and more exhaustive description of botanical material is available that can be tested using modern scientific methods.
Ayurveda and Chinese medical systems thus have an important role in bioprospecting of new medicines. Serendipity and synthetic dominancePharmaceutical research took a major leap when alongside natural products chemistry, pharmacologists, microbiologists and biochemists began to unravel the chemistry of natural processes in human, animals, plants and microorganisms.
Advances in synthetic organic chemistry led to the identification of many key chemical molecules that offered more opportunities to develop novel compounds. Many new drugs emerged by this route, particularly those now being used to treat infections, infestations, cancers, ulcers, heart and blood pressure conditions. Many drugs were developed through random screening of thousands of chemicals synthesized as dye-stuffs and the like; many others resulted from serendipity happy chance arising from sharp-eyed observations of physicians and scientists.
Examples of such drugs include sulphonamides, isoniazid, anti-psychotics, anti-histamines and penicillin. Emergence of the modern pharmaceutical industry is an outcome of all these different activities that developed potent single molecules with highly selective activity for a wide variety of ailments.
The drugs produced in many cases improved on nature, viz. These successes and many more like them resulted in reduced interest in natural products drug discovery and many major drug companies almost neglected such divisions.
Work on developing new drugs for the treatment of the world's major diseases, malaria, trypanosomiasis, filariasis, tuberculosis, schistosomiasis, leshmaniasis and amoebiasis came almost to a standstill. In addition, although botanical medications continued to be produced in every country, the clinical efficacy of these was usually not evaluated and the composition of these complex mixtures was only crudely analysed. Thus, herbal medicines became the domain of 'old wives' tales' and quack medicine, exploitation of the sick, the desperate and the gullible.
Sadly, herbal medicines continued to reflect poor quality control both for materials and clinical efficacy. Back to traditional wisdomLag phase for botanical medicine is now rapidly changing for a number of reasons. Problems with drug-resistant microorganisms, side effects of modern drugs, and emerging diseases where no medicines are available, have stimulated renewed interest in plants as a significant source of new medicines.
Pharmaceutical scientists are experiencing difficulty in identifying new lead structures, templates and scaffolds in the finite world of chemical diversity. A number of synthetic drugs have adverse and unacceptable side effects. There have been impressive successes with botanical medicines, most notably quinghaosu, artemisinin from Chinese medicine. Considerable research on pharmacognosy, chemistry, pharmacology and clinical therapeutics has been carried out on ayurvedic medicinal plants 3.
Numerous molecules have come out of ayurvedic experiential base, examples include rauwolfia alkaloids for hypertension, psoralens in vitiligo, holarrhena alkaloids in amoebiasis, guggulsterons as hypolipidemic agents, mucuna pruriens for Parkinson's disease, piperidines as bioavailability enhancers, baccosides in mental retention, picrosides in hepatic protection, phyllanthins as antivirals, curcumine in inflammation, withanolides, and many other steroidal lactones and glycosides as immunomodulators 4.
A whole range of chronic and difficult-to-treat diseases such as cancers, cardiovascular disease, diabetes, rheumatism and AIDS, all require new effective drugs. Most developing countries have relied and will continue to rely on traditional natural medicines due to the deterrence of high costs of modern allopathic medicines. The current scope of this article prevents a comprehensive discussion of alternative and complementary medicine CAM. Every medical system or therapy has certain advantages and limitations.
Modern medicine is no exception to this 6. Botanical medicine: research, development and marketsThirty per cent of the worldwide sales of drugs is based on natural products. Though recombinant proteins and peptides account for increasing sales rates, the superiority of low-molecular mass compounds in human disease therapy remains undisputed mainly due to more favourable compliance and bioavailability properties.
Approaches to improve and accelerate the joint drug discovery and development process are expected to take place mainly from innovation in drug target elucidation and lead structure discovery. Therefore, the need for new concepts to generate collection of large compounds with improved structural diversity has been correctly emphasized by Grabley and Thiericke 5.
There are number of problems connected with the search for new prototype drugs of biological origin. Investigations of plants used in traditional and modern medicine in China serve as a source of inspiration and as models for the synthesis of new drugs with better therapeutic, chemical or physical properties than the original compounds 7.
The World Health Organization also has recognized the importance of traditional medicine and has been active in creating strategies, guidelines and standards for botanical medicines 8. Lilly Research Laboratories markets several million dollars worth of vincristine and vinblastine -the periwinkle derivatives used to treat childhood leukaemia and Hodgkin's disease.
China, Germany, India and Japan, among others, are also screening wild species for new drugs. Proven agro-industrial technologies need to be applied to the cultivation and processing of medicinal plants and the manufacture of herbal medicines The mass screen-ing of plants in the search for new drugs is vastly expensive and inefficient. It would be cheaper and perhaps more productive to re-examine plant remedies described in ancient and medieval texts Many higher plants produce economically important organic compounds such as oils, resins, tannins, natural rubber, gums, waxes, dyes, flavours, fragrances, pharmaceuticals and pesticides.
Advances in biotechnology, particularly methods for culturing plant cells and tissues, should provide new means for the commercial processing of even rare plants and the chemicals that they produce.
Context: In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics. Aim: We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia. Method: We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents.
Natural products have been the single most productive source of leads for the development of drugs. Over a new products are in clinical.
Natural Products and Drug Discovery: An Integrated Approach provides an applied overview of the field, from traditional medicinal targets, to cutting-edge molecular techniques. Natural products have always been of key importance to drug discovery, but as modern techniques and technologies have allowed researchers to identify, isolate, extract and synthesize their active compounds in new ways, they are once again coming to the forefront of drug discovery. Combining the potential of traditional medicine with the refinement of modern chemical technology, the use of natural products as the basis for drugs can help in the development of more environmentally sound, economical, and effective drug discovery processes. Section I: Traditional medicine and Drug discovery 1.
Natural products and their related moieties have historically been incredible as a source of therapeutic agents.
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A huge number of natural product-derived compounds in various stages of clinical development highlight the existing viability and significance of.
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The revolution in biology over the past two decades has resulted in radical new opportunities for discovery of new drugs. Most importantly, it has defined major drug targets in the form of molecular components of disease processes.
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