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Screening can distinguish compounds that independently induce immune responses from those that do so exclusively in the presence of some pathogen. Independent activators can be toxic to cells. Others enhance resistance only in the presence of pathogens. In 2012, five activators that protected against
244:
techniques have provided agrochemists with a method for validating potential new biochemical targets. However, genes such as avirulence genes are not essential for the organism and many potential targets lack known inhibitors. Examples of this procedure include the search for new herbicidal compounds
233:
three-dimensional (3D) shape, atom-type similarity, or 2D extended connectivity fingerprints also retrieve molecules of interest out of a database with a useful success rate. Scaffold-hopping is also efficiently achieved by virtual screening, with 2D and 3D variants providing the best results.
232:
was generated by keeping the core scaffold constant and attaching different linkers. The scores obtained from docking studies ranked these molecules. Resulting novel compounds showed a primary hit rate of 10.9%, much higher than for conventional high-throughput screening. Other tools like
76:
The rate of new molecule introductions has declined. The costs to bring a new molecule to market have risen from U.S. $ 152 million in 1995 to $ 256 million in 2005, as the number of compounds synthesized to deliver one new market introduction rose from 52,500 in 1995 to 140,000 in 2005.
130:
antimycotics or fungicides. However, the chemical environments encountered en route from the application site to the target generally require differing physicochemical properties, while the unit costs are generally much lower. Agrochemicals typically have a lower number of
167:
Structure-based design is appealing for crop researchers because of the many protein structures in the public domain, which increased from 13,600 to 92,700 between 200 and 2013. Many agrochemical crystals are now in the public domain. The structures of several interesting
135:
donors. For example, over 70% of insecticides have no hydrogen bond donor, and over 90% of herbicides have two or fewer. Desirable agrochemicals have residual activity and persistence of effect lasting up to several weeks to allow large spray intervals. The majority of
53:
Along with improved agrochemicals, seeds, fertilizers, mechanization, and precision farming, improved protection of crops from weeds, insects and other threats is highly sought. Developments over the past 1960–2013 period enabled reduced use rates, in the cases of the
227:
The likelihood of finding active analogs on the basis of a screen hit from a novel scaffold can be increased by virtual screening. Because the pharmacophore of the reference ligand is well defined, a virtual library of potential herbicidal inhibitors of the enzyme
155:
is a multidisciplinary process that is relatively new in agrochemicals. As of 2013 no products on the market were the direct result of this approach. However, discovery programs have benefited from structure-based design, including that for
208:, virtual screening and genome sequencing have helped generate drug leads. Published examples of fragment-based agrochemical design have been comparatively rare, although the method was used to generate new ACC inhibitors. A combination of
268:
Plant activators are compounds that activate a plant's immune system in response to invasion by pathogens. They play a crucial role in crop survival. Unlike pesticides, plant activators are not pathogen specific and are not affected by
245:
of the nonmevalonate, such as the discovery of new inhibitors of 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD, Enzyme
Commission (EC) number 2.7.7.60) with the best expressing a half-maximal inhibitory concentration (
260:(SHMT) inhibitors were also found. Three hundred thousand compounds were tested against the SHMT enzyme, producing 24 hits. Among those hits, a subclass was followed with in vivo screening and compounds were promoted to field trials.
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The activation of plant responses is often associated with arrested growth and reductions in yield, for reasons that remain unclear. The molecular mechanisms governing plant activators are largely unknown.
100:
Candidate molecules are optimized through a design-synthesis-test-analysis cycle. While compounds eventually are tested on the target organism(s). However, in vitro assays are becoming more common.
34:
has focused on developing molecules that combine low use rates and that are more selective, safer, resistance-breaking and cost-effective. Obstacles include increasing
84:(EPA) over the 1997–2010 period included biological (B), natural product (NP), synthetic (S) and synthetic natural derived (SND) substances. Combining conventional
287:
bacteria by priming immune response without directly activating defense genes. The compounds inhibit two enzymes that inactivate the defense hormone
552:"Novel plant immune-priming compounds identified via high-throughput chemical screening target salicylic acid glucosyltransferases in Arabidopsis"
273:, making them ideal for use in agriculture. Wet-rice farmers across East Asia use plant activators as a sustainable means to enhance crop health.
550:
Noutoshi Y, Okazaki M, Kida T, Nishina Y, Morishita Y, Ogawa T, Suzuki H, Shibata D, Jikumaru Y, Hanada A, Kamiya Y, Shirasu K (September 2012).
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45:
libraries, intermediates from projects in other indications and compound collections from pharmaceutical and animal health companies.
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335:
Lamberth C, Jeanmart S, Luksch T, Plant A (August 2013). "Current challenges and trends in the discovery of agrochemicals".
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17:
92:, NPs accounted for the majority of registrations, with 35.7%, followed by S with 30.7%, B with 27.4% and SND with 6.1%.
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was reported in 2011 and represents a starting point for the design of novel insecticides. This structure led to a
999:
257:
81:
450:"Physical and Molecular Properties of Agrochemicals: An Analysis of Screen Inputs, Hits, Leads, and Products"
253:, IspD enzyme cocrystallized with the inhibitor, a more potent inhibitor with an IC50 of 35 nM was designed.
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249:) of 140 nM in the greenhouse at 3 kg/ha (2.7 lb/acre). Thanks to an x-ray crystal structure of
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The sources of new molecules employ natural products, competitors, universities, chemical vendors,
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Lindell SD, Pattenden LC, Shannon J (June 2009). "Combinatorial chemistry in the agrosciences".
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Cantrell CL, Dayan FE, Duke SO (June 2012). "Natural products as sources for new pesticides".
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crystal structures yielded synthetically amenable compounds. Common to all inhibitors is the
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is addressed, and can potentially be of use in both contexts. One example is the
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10.1002/(SICI)1521-3773(20000515)39:10<1724::AID-ANIE1724>3.0.CO;2-5
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Stetter J, Lieb F (2000). "Innovation in Crop
Protection: Trends in Research".
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fungicides. Fragments were linked to the warhead to form a virtual library.
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Klebe G (2000). "Recent developments in structure-based drug design".
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are now in the public domain. For example, the crystal structure of a
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220:"warhead", whose interactions and position are well known from the
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530:"Screening technique uncovers five new plant activator compounds"
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73:, reaching 99%, with concomitant environmental improvements.
656:"Chemical crop protection research. Methods and challenges"
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may operate via the same processes. In several cases, a
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and an increasingly stringent regulatory environment.
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295:or SAGTs), providing enhanced disease resistance.
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80:New active ingredient registrations with the US
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27:Scientific researches on pesticides
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200:Fragment- and target-based design
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258:serine hydroxymethyltransferase
82:Environmental Protection Agency
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448:Clarke ED, Delaney JS (2003).
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104:Parallels with pharmaceuticals
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483:Journal of Molecular Medicine
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61:(5), the piperidinylthiazole
875:Persistent organic pollutant
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1018:Index of pesticide articles
845:Agricultural spray adjuvant
610:. Nova Science Publishers.
415:Journal of Natural Products
212:fragment-based design with
140:found in agrochemicals are
30:Early twenty-first century
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1013:Integrated Pest Management
860:Integrated pest management
660:Pure and Applied Chemistry
467:10.2533/000942903777678641
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910:Paradox of the pesticides
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607:Pesticide research trends
392:10.1016/j.bmc.2009.03.027
950:Pesticide Action Network
870:Non-pesticide management
604:Tennefy AB (June 2008).
850:Biological pest control
673:10.1351/pac200274122241
349:10.1126/science.1237227
43:combinatorial chemistry
963:The Pesticide Question
568:10.1105/tpc.112.098343
188:model for a related γ-
153:Structure-based design
148:Structure-based design
865:Maximum residue limit
835:Environmental effects
495:10.1007/s001090000084
230:anthranilate synthase
206:fragment-based design
158:scytalone dehydratase
1023:Pesticide categories
293:glucosyltransferases
251:Arabidopsis thaliana
65:, and the emamectin
36:pesticide resistance
18:Insecticide research
242:antisense knockdown
236:Genome-sequencing,
204:Techniques such as
32:pesticide research
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666:(12): 2241–2246.
654:Müller U (2002).
633:(10): 1724–1744.
617:978-1-60456-200-2
427:10.1021/np300024u
190:aminobutyric acid
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56:sulfonylurea
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900:Degradation
895:Formulation
885:Application
800:Rodenticide
780:Insecticide
743:Bactericide
284:Pseudomonas
222:strobilurin
1049:Pesticides
1038:Categories
978:By country
935:Resurgence
930:Resistance
840:Fumigation
790:Nematicide
721:Pesticides
536:2014-02-11
532:. Phys.org
299:References
182:ivermectin
162:rice blast
117:homologous
86:pesticides
71:acaricides
63:fungicides
59:herbicides
915:Poisoning
805:Slimicide
795:Piscicide
773:Defoliant
768:Herbicide
763:Fungicide
738:Acaricide
729:Pesticide
365:206548681
210:in silico
174:glutamate
920:Research
682:96664327
647:10934351
586:22960909
511:21314020
503:10954199
435:22616957
400:19349185
357:23950530
186:homology
128:triazole
124:receptor
925:Residue
748:Biocide
577:3480303
337:Science
176:-gated
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612:ISBN
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499:PMID
431:PMID
396:PMID
353:PMID
291:(SA
247:IC50
194:GABA
111:and
88:and
69:and
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