lead discovery process, natural products still play a major role as starting material for drug discovery. a 2007 report found that of the 974 small molecule new chemical entities developed between 1981 and 2006, 63% were natural derived or semisynthetic derivatives of natural products. for certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. in many cases, these products have been used traditionally for many years. natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies. plant-derived further information: medicinal plant many secondary metabolites produced by plants have potential therapeutic medicinal properties. these secondary metabolites contain, bind to, and modify the function of proteins (receptors, enzymes, etc.). consequently, plant derived natural products have often been used as the starting point for drug discovery. history main article: history of pharmacy until the renaissance, the vast majority of drugs in western medicine were plant-derived extracts. this has resulted in a pool of information about the potential of plant species as important sources of starting materials for drug discovery. botanical knowledge about different metabolites and hormones that are produced in different anatomical parts of the plant (e.g. roots, leaves, and flowers) are crucial for correctly identifying bioactive and pharmacological plant properties. identifying new drugs and getting them approved for market has proved to be a stringent process due to regulations set by national drug regulatory agencies. jasmonates chemical structure of methyl jasmonate (ja). jasmonates are important in responses to injury and intracellular signals. they induce apoptosis and protein cascade via proteinase inhibitor, have defense functions, and regulate plant responses to different biotic and abiotic stresses. jasmonates also have the ability to directly act on mitochondrial membranes by inducing membrane depolarization via release of metabolites. jasmonate derivatives (jad) are also important in wound response and tissue regeneration in plant cells. they have also been identified to have anti-aging effects on human epidermal layer. it is suspected that they interact with proteoglycans (pg) and glycosaminoglycan (gag) polysaccharides, which are essential extracellular matrix (ecm) components to help remodel the ecm. the discovery of jads on skin repair has introduced newfound interest in the effects of these plant hormones in therapeutic medicinal application. salicylates chemical structure of acetylsalicylic acid, more commonly known as aspirin. salicylic acid (sa), a phytohormone, was initially derived from willow bark and has since been identified in many species. it is an important player in plant immunity, although its role is still not fully understood by scientists. they are involved in disease and immunity responses in plant and animal tissues. they have salicylic acid binding proteins (sabps) that have shown to affect multiple animal tissues. the first discovered medicinal properties of the isolated compound was involved in pain and fever management. they also play an active role in the suppression of cell proliferation. they have the ability to induce death in lymphoblastic leukemia and other human cancer cells. one of the most common drugs derived from salicylates is aspirin, also known as acetylsalicylic acid, with anti-inflammatory and anti-pyretic properties. animal-derived some drugs used in modern medicine have been discovered in animals or are based on compounds found in animals. for example, the anticoagulant drugs, hirudin and its synthetic congener, bivalirudin, are based on saliva chemistry of the leech, hirudo medicinalis. used to treat type 2 diabetes, exenatide was developed from saliva compounds of the gila monster, a venomous lizard. microbial metabolites microbes compete for living space and nutrients. to survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. microbes are the main source of antimicrobial drugs. streptomyces isolates have been such a valuable source of antibiotics, that they have been called medicinal molds. the classic example of an antibiotic discovered as a defense mechanism against another microbe is penicillin in bacterial cultures contaminated by penicillium fungi in 1928. marine invertebrates main article: sponge isolates marine environments are potential sources for new bioactive agents. arabinose nucleosides discovered from marine invertebrates in 1950s, demonstrated for the first time that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. it took until 2004 when the first marine-derived drug was approved. for example, the cone snail toxin ziconotide, also known as prialt treats severe neuropathic pain. several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. one class of these agents are bryostatin-like compounds, under investigation as anti-cancer therapy. chemical diversity as above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. however, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached. this has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. the chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. the synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much greater chemical diversity, distributing more evenly to the chemical space. the most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). other chemical differences between these two groups include the nature of heteroatoms (o and n enriched in natural products, and s and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). as both structure rigidity and chirality are well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourably to today's combinatorial chemistry libraries as potential lead molecules. screening two main approaches exist for the finding of new bioactive chemical entities from natural sources. the first is sometimes referred to as random collection and screening of material, but the collection is far from random. biological (often botanical) knowledge is often used to identify families that show promise. this approach is effective because only a small part of the earth's biodiversity has ever been tested for pharmaceutical activity. also, organisms living in a species-rich environment need to evolve defensive and competitive mechanisms to survive. those mechanisms might be exploited in the development of beneficial drugs. a collection of plant, animal and microbial samples from rich ecosystems can potentially give rise to novel biological activities worth exploiting in the drug development process. one example of successful use of this strategy is the screening for antitumor agents by the national cancer institute, which started in the 1960s. paclitaxel was identified from pacific yew tree taxus brevifolia. paclitaxel showed anti-tumour activity by a previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast, and ovarian cancer, as well as for kaposi's sarcoma. early in the 21st century, cabazitaxel (made by sanofi, a french firm), another relative of taxol has been shown effective against prostate cancer, also because it works by preventing the formation of microtubules, which pull the chromosomes apart in dividing cells (such as cancer cells). other examples are: 1. camptotheca (camptothecin · topotecan · irinotecan · rubitecan · belotecan); 2. podophyllum (etoposide · teniposide); 3a. anthracyclines (aclarubicin · daunorubicin · doxorubicin · epirubicin · idarubicin · amrubicin · pirarubicin · valrubicin · zorubicin); 3b. anthracenediones (mitoxantrone · pixantrone). the second main approach involves ethnobotany, the study of the general use of plants in society, and ethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses. artemisinin, an antimalarial agent from sweet wormtree artemisia annua, used in chinese medicine since 200bc is one drug used as part of combination therapy for multiresistant plasmodium falciparum. structural elucidation the elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. mass spectrometry is a method in which individual compounds are identified based on their mass/charge ratio, after ionization. chemical compounds exist in nature as mixtures, so the combination of liquid chromatography and mass spectrometry (lc-ms) is often used to separate the individual chemicals. databases of mass spectras for known compounds are available and can be used to assign a structure to an unknown mass spectrum. nuclear magnetic resonance spectroscopy is the primary technique for determining chemical structures of natural products. nmr yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule's architecture. new drug application when a drug is developed with evidence throughout its history of research to show it is safe and effective for the intended use in the united states, the company can file an application – the new drug application (nda) – to have the drug commercialized and available for clinical application. nda status enables the fda to examine all submitted data on the drug to reach a decision on whether to approve or not approve the drug candidate based on its safety, specificity of effect, and efficacy of doses.