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1.
Biol Chem ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31408429

RESUMO

Succinate dehydrogenase (SDH), complex II or succinate:quinone oxidoreductase (SQR) is a crucial enzyme involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), the two primary metabolic pathways for generating ATP. Impaired function of SDH results in deleterious disorders from cancer to neurodegeneration. SDH function is tailored to meet the energy demands in different cell types. Thus, understanding how SDH function is regulated and how it operates in distinct cell types can support the development of therapeutic approaches against the diseases. In this article we discuss the molecular pathways which regulate SDH function and describe extra roles played by SDH in specific cell types.

2.
Pest Manag Sci ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31347760

RESUMO

BACKGROUND: ß-Sitosterol is a plant metabolite with a broad range of anti-fungal activity, however, this compound is not toxic against a few fungal species. The target of ß-sitosterol and the nature of its selective toxicity are not yet clear. Using a yeast model system and taking advantage of molecular biology and computational approaches, we identify the target and explain why ß-sitosterol is not toxic against some fungal pathogens. RESULTS: ß-Sitosterol (200 µg mL-1 ) is toxic against yeast cells expressing only Osh4 (an oxysterol-binding protein) and harbouring a upc2-1 mutation (which enables sterol uptake), but not against yeast strains expressing all seven Osh proteins and harbouring a upc2-1 mutation. Furthermore, ß-sitosterol is not toxic against yeast strains without the upc2-1 mutation irrespective of the number of Osh proteins being expressed. The deletion of COQ1 (a gene known to be highly induced upon deletion of OSH4) enhances the toxicity of ß-sitosterol in yeast cells expressing only Osh4 and harbouring the upc2-1 mutation. Molecular modelling suggests that ß-sitosterol binds to Osh4 and the binding mode is similar to the binding of cholesterol to Osh4. CONCLUSION: Our results indicate that the concentrations of ß-sitosterol, and Osh4, as well as its homologues within cells, are most likely the main determinants of ß-sitosterol toxicity. Furthermore, some fungal species do not take up sterols, e.g. Saccharomyces cerevisiae, under aerobic conditions. Therefore, sterol uptake may also contribute to the ß-sitosterol anti-fungal effect. These findings enable predicting the toxicity of ß-sitosterol against plant fungal pathogens. © 2019 Society of Chemical Industry.

3.
Eur J Med Chem ; 178: 705-714, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229873

RESUMO

As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.

4.
Cell Mol Life Sci ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236625

RESUMO

Succinate dehydrogenase (SDH) also known as complex II or succinate:quinone oxidoreductase is an enzyme involved in both oxidative phosphorylation and tricarboxylic acid cycle; the processes that generate energy. SDH is a multi-subunit enzyme which requires a series of proteins for its proper assembly at several steps. This enzyme has medical significance as there is a broad range of human diseases from cancers to neurodegeneration related to SDH malfunction. Some of these disorders have recently been linked to defective assembly factors, reinvigorating further research in this area. Apart from that this enzyme has agricultural importance as many fungicides have been/will be designed targeting specifically this enzyme in plant fungal pathogens. In addition, we speculate it might be possible to design novel fungicides specifically targeting fungal assembly factors. Considering the medical and agricultural implications of SDH, the aim of this review is an overview of the SDH assembly factors and critical analysis of controversial issues around them.

5.
J Agric Food Chem ; 67(18): 5072-5084, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30986354

RESUMO

Alternative splicing (AS), the process of removing introns from pre-mRNA and the rearrangement of exons to produce several types of mature transcripts, is a remarkable step preceding protein synthesis. In particular, it has now been conclusively shown that up to ∼95% of genes are alternatively spliced to generate a complex and diverse proteome in eukaryotic organisms. Consequently, AS is one of the determinants of the functional repertoire of cells. Many studies have revealed that AS in plants can be regulated by cell type, developmental stage, environmental stress, and the circadian clock. Moreover, increasing amounts of evidence reveal that chemical compounds can affect various steps during splicing to induce major effects on plant physiology. Hence, the chemical modulation of AS can serve as a good strategy for molecular-target identification in attempts to potentially control plant genetics. However, the kind of mechanisms involved in the chemical modulation of AS that can be used in agrochemical research remain largely unknown. This review introduces recent studies describing the specific roles AS plays in plant adaptation to environmental stressors and in the regulation of development. We also discuss recent advances in small molecules that induce alterations of AS and the possibility of using this strategy in agrochemical-target identification, giving a new direction for potential genetic control in agrochemical research.


Assuntos
Agroquímicos/farmacologia , Processamento Alternativo , Plantas/efeitos dos fármacos , Plantas/genética , Processamento Alternativo/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Desenvolvimento Vegetal/efeitos dos fármacos , Plantas/química , Plantas/metabolismo , RNA de Plantas/genética
6.
Planta ; 249(6): 1997-2014, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30904945

RESUMO

MAIN CONCLUSION: The work offers a comprehensive evaluation on the phylogenetics and conservation of splicing patterns of the plant SPF30 splicing factor gene family. In eukaryotes, one pre-mRNA can generate multiple mRNA transcripts by alternative splicing (AS), which expands transcriptome and proteome diversity. Splicing factor 30 (SPF30), also known as survival motor neuron domain containing protein 1 (SMNDC1), is a spliceosomal protein that plays an essential role in spliceosomal assembly. Although SPF30 genes have been well characterised in human and yeast, little is known about their homologues in plants. Here, we report the genome-wide identification and phylogenetic analysis of SPF30 genes in the plant kingdom. In total, 82 SPF30 genes were found in 64 plant species from algae to land plants. Alternative transcripts were found in many SPF30 genes and splicing profile analysis revealed that the second intron in SPF30 genome is frequently associated with AS events and contributed to the birth of novel exons in a few SPF30 members. In addition, different conserved sequences were observed at these putative splice sites among moss, monocots and dicots, respectively. Our findings will facilitate further functional characterization of plant SPF30 genes as putative splicing factors.


Assuntos
Processamento Alternativo/genética , Plantas/genética , Precursores de RNA/genética , Fatores de Processamento de RNA/genética , Evolução Biológica , Sequência Conservada , Éxons/genética , Íntrons/genética , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , RNA de Plantas/genética , Spliceossomos/genética , Spliceossomos/metabolismo
7.
Food Chem ; 275: 688-695, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724249

RESUMO

A novel solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) method was developed to quantify two new fungicide residuals (Y13149, Y12196) in mung bean sprouts. With a stable and biocompatible elcetrospinning nanofiber (polystyrene/graphene@silica, PS/G@SiO2) as coating, the SPME fiber was directly inserted into the stem of mung bean sprout to in-situ in-vivo sampling and extraction, followed by GC-MS analysis. Under the optimal conditions, satisfactory average recoveries of 99% and 72% were obtained for Y13149 and Y12196 with the relative standard deviations (RSDs) under 16.3%, indicating good precision and anti-matrix ability of the method. The result also exhibited low detection limit (0.06-0.08 µg·L-1) and wide liner range (0.3-100 µg·L-1) with the correlation coefficients (R2) of 0.9989. The established method was applied successfully to trace the accumulation and distribution of fungicides in mung bean sprouts, and it provides a simple, rapid and reliable quantitative method for food analysis.


Assuntos
Fungicidas Industriais/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Vigna/química , Análise de Alimentos , Fungicidas Industriais/isolamento & purificação , Grafite/química , Limite de Detecção , Nanofibras/química , Poliestirenos/química , Dióxido de Silício/química , Microextração em Fase Sólida , Vigna/metabolismo
8.
J Agric Food Chem ; 67(10): 2774-2781, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30794394

RESUMO

The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (Δ Gcal) of the newly synthesized analogues correlated very well ( R2 = 0.90) with their experimental binding free energies (Δ Gexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.


Assuntos
Produtos Biológicos/química , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/química , Macrolídeos/química , Animais , Sítios de Ligação , Complexo III da Cadeia de Transporte de Elétrons/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Poríferos/química
9.
J Chem Inf Model ; 59(2): 630-635, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30620565

RESUMO

The concept of insecticide-likeness is valuable to select more promising lead candidates during the early stages of drug discovery. We analyzed the physicochemical properties of commercial insecticides and optimized available drug-likeness scoring functions to quantitatively evaluate the insecticidal-like potential of compounds. An interactive platform named Insecticide Physicochemical-properties Analysis Database (InsectiPAD) was developed, which covers 495 approved insecticides and over 22 200 related physicochemical properties. More importantly, it contains over 2900 qualitative analyses and 1500 quantitative scores for insecticides and provides comprehensive insecticide-likeness analysis for any compound. The accuracy and ability of InsectiPAD to distinguish known insecticides (positive sample) from other compounds (negative sample) was also assessed, which is around 75%. Simple input and efficient interpretation are ensured to be useful and helpful for insecticide discovery.

10.
Anal Chem ; 91(6): 3877-3884, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30626182

RESUMO

Neutrophil elastase (NE), a typical hematopoietic serine protease, has significant roles in inflammatory and immune responses, and thus is highly associated with various diseases such as acute lung injury (ALI) and lung cancer. Rapid and accurate measurement of NE activity in biological systems is particularly important for understanding the role of NE in inflammatory diseases, as well as clinical diagnosis. However, the specific detection and noninvasive imaging of NE in vivo remains a challenge. To address this issue, a small-molecule substrate based near-infrared fluorogenic probe (NEP) for NE was constructed via incorporating pentafluoroethyl as the recognition group with a hemicyanine dye-based fluorophore. This initially quenched probe possesses more than 25-fold red fluorescence enhancement upon the catalysis of human NE, and the detection limit is about 29.6 ng/mL. In addition, the high specificity and the long emission wavelength (λemmax = 700 nm) of NEP allowed the direct monitoring of NE-trafficking, exogenous NE uptake, and endogenous NE upregulation at the cellular level. Moreover, the successful spatiotemporal imaging of NE in ALI model mice also made it a promising new tool in clinical diagnosis for ALI and other lung diseases.

11.
FEBS J ; 286(5): 975-990, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632699

RESUMO

Slow-binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off-target rates is restricted by a limited understanding of the structural basis of slow-binding inhibition kinetics in enzyme-drug interactions. 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time-dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow-binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C-terminal α-helix in the inhibitor-bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time-dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD-targeted drugs or herbicides with longer target residence time and improved properties. DATABASE: Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).

12.
Eur J Med Chem ; 166: 22-31, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684868

RESUMO

Involved in the tyrosine degradation pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 µM) with about 2-fold more potent than NTBC (IC50 = 0.085 µM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Cicloexanonas/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Nitrobenzoatos/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Domínio Catalítico , Cicloexanonas/química , Cicloexanonas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Nitrobenzoatos/química , Nitrobenzoatos/metabolismo , Relação Estrutura-Atividade
13.
J Agric Food Chem ; 67(7): 1823-1830, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30677302

RESUMO

The increasing prevalence of fungal diseases, continual development of resistance, and stringent environmental regulations have revealed an urgent need to develop more selective, safer, resistance-breaking, and cost-effective fungicides. However, most new fungicidal lead compounds fail in their late stages of development as a result of poor solubility or permeability, meaning that they have suboptimal physicochemical properties. Hence, the exploration of advanced technologies for compound "fungicide-likeness" assessment might overcome these obstacles and bring more chemical entities to market. FungiPAD ( http://chemyang.ccnu.edu.cn/ccb/database/FungiPAD/ ) is a free platform employed to predict physicochemical properties, bioavailability, and fungicide-likeness swiftly and powerfully using comprehensive approaches, such as physicochemical radars and qualitative and quantitative analyses. This platform contains data for over 16 000 physicochemical descriptors and the results of 2200 qualitative and 1100 quantitative analyses of marketed fungicides and provides comprehensive fungicide-likeness analysis for different compounds. The user-friendly interface facilitates interpretation and manipulation by non-computational scientists in support of fungicide discovery.


Assuntos
Fungicidas Industriais/química , Internet , Disponibilidade Biológica , Fenômenos Químicos , Bases de Dados de Compostos Químicos , Desenvolvimento de Medicamentos , Estudos de Avaliação como Assunto , Fungicidas Industriais/farmacologia , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Equivalência Terapêutica
14.
Brief Bioinform ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30496338

RESUMO

Drug resistance is one of the most intractable issues for successful treatment in current clinical practice. Although many mutations contributing to drug resistance have been identified, the relationship between the mutations and the related pharmacological profile of drug candidates has yet to be fully elucidated, which is valuable both for the molecular dissection of drug resistance mechanisms and for suggestion of promising treatment strategies to counter resistant. Hence, effective prediction approach for estimating the sensitivity of mutations to agents is a new opportunity that counters drug resistance and creates a high interest in pharmaceutical research. However, this task is always hampered by limited known resistance training samples and accurately estimation of binding affinity. Upon this challenge, we successfully developed Auto In Silico Macromolecular Mutation Scanning (AIMMS), a web server for computer-aided de novo drug resistance prediction for any ligand-protein systems. AIMMS can qualitatively estimate the free energy consequences of any mutations through a fast mutagenesis scanning calculation based on a single molecular dynamics trajectory, which is differentiated with other web services by a statistical learning system. AIMMS suite is available at http://chemyang.ccnu.edu.cn/ccb/server/AIMMS/.

15.
Planta ; 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30317439

RESUMO

MAIN CONCLUSION: This study systematically identifies plant SYF2/NTC31/p29 genes from 62 plant species by a combinatory bioinformatics approach, revealing the importance of this gene family in phylogenetics, duplication, transcriptional, and post-transcriptional regulation. Alternative splicing is a post-transcriptional regulatory mechanism, which is critical for plant development and stress responses. The entire process is strictly attenuated by a complex of splicing-related proteins, designated splicing factors. Human p29, also referred to as synthetic lethal with cdc forty 2 (SYF2) or the NineTeen complex 31 (NTC31), is a core protein found in the NTC complex of humans and yeast. This splicing factor participates in a variety of biological processes, including DNA damage repair, control of the cell cycle, splicing, and tumorigenesis. However, its function in plants has been seldom reported. Thus, we have systematically identified 89 putative plant SYF2s from 62 plant species among the deposited entries in the Phytozome database. The phylogenetic relationships and evolutionary history among these plant SYF2s were carefully examined. The results revealed that plant SYF2s exhibited distinct patterns regarding their gene structure, promoter sequences, and expression levels, suggesting their functional diversity in response to developmental cues or stress treatments. Although local duplication events, such as tandem duplication and retrotransposition, were found among several plant species, most of the plant species contained only one copy of SYF2, suggesting the existence of additional mechanisms to confer duplication resistance. Further investigation using the model dicot and monocot representatives Arabidopsis and rice SYF2s indicated that the splicing pattern and resulting protein isoforms might play an alternative role in the functional diversity.

16.
ACS Sens ; 3(10): 2118-2128, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30203965

RESUMO

Butyrylcholinesterase (BChE) is widely distributed in various tissues and highly implicated in several important human diseases, especially Alzheimer's disease (AD). However, the role of BChE in AD is still controversial, which may be partially attributed to the lack of a direct tool for real-time and noninvasive monitoring of BChE in in vivo. Here, we report three rationally designed near-infrared fluorogenic probes that possess excellent discrimination for butyrylcholinesterase (BChE) over the related enzyme acetylcholinesterase (AChE). The refined probe, BChE-NIRFP, not only functions as an exquisite substrate for BChE in in vitro assays but also represents a superb "signal-on" imaging tool to real-time track BChE levels in human cells, zebrafish, and a mouse model of AD. A further application of BChE-NIRFP to identify the cellular mechanism reveals that Aß fibrils and insulin resistance may be important contributors to the abnormally elevated BChE levels observed during AD progression. Based on the results from the present study, this new probe is a valuable tool for basic and clinical research designed to obtain a complete understanding of the physiological roles of BChE in diverse human diseases, particularly AD.

17.
J Chem Inf Model ; 58(9): 1725-1730, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30134653

RESUMO

Structural analyses of drugs and pesticides can enable the identification of new bioactive compounds with novel and diverse scaffolds as well as improve our understanding of the bioactive fragment space. The Pesticide And Drug Fragments (PADFrag) database is a unique bioinformatic-cheminformatic cross-referencing resource that combines detailed bioactive fragment data and potential targets with a strong focus on quantitative, analytic, and molecular-scale information for the exploration of bioactive fragment space for drug discovery ( http://chemyang.ccnu.edu.cn/ccb/database/PADFrag/ ). The main applications of PADFrag are the analysis of the privileged structures within known bioactive molecules, ab initio molecule library design, and core fragment discovery for fragment-based drug design. Other potential applications include prediction of fragment interactions and general pharmaceutical research.

18.
J Agric Food Chem ; 66(34): 8914-8934, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30060657

RESUMO

Pd-catalyzed cross-coupling reactions have become essential tools for the construction of carbon-carbon and carbon-heteroatom bonds. Over the last three decades, great efforts have been made with cross-coupling chemistry in the discovery, development, and commercialization of innovative new pharmaceuticals and agrochemicals (mainly herbicides, fungicides, and insecticides). In view of the growing interest in both modern crop protection and cross-coupling chemistry, this review gives a comprehensive overview of the successful applications of various Pd-catalyzed cross-coupling methodologies, which have been implemented as key steps in the synthesis of agrochemicals (on R&D and pilot-plant scales) such as the Heck, Suzuki, Sonogashira, Stille, and Negishi reactions, as well as decarboxylative, carbonylative, α-arylative, and carbon-nitrogen bond bond-forming cross-coupling reactions. Some perspectives and challenges for these catalytic coupling processes in the discovery of agrochemicals are briefly discussed in the final section. The examples chosen demonstrate that cross-coupling chemistry approaches open-up new, low-cost, and more efficient industrial routes to existing agrochemicals, and such methods also have the capability to lead the new generation of pesticides with novel modes of action for sustainable crop protection.


Assuntos
Agroquímicos/síntese química , Reagentes para Ligações Cruzadas/química , Paládio/química , Agroquímicos/química , Catálise , Estrutura Molecular
19.
Curr Med Chem ; 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29737247

RESUMO

BACKGROUND: In silico drug discovery has been proved to be a solidly established key component in early drug discovery. However, this task is hampered by the limitation of quantity and quality of compound databases for screening. In order to overcome these obstacles, freely accessible database resources of compounds have bloomed in recent years. Nevertheless, how to choose appropriate tools to treat these freely accessible databases are crucial. To the best of our knowledge, this is the first systematic review on this issue. OBJECTIVE: The existed advantages and drawbacks of chemical databases were analyzed and summarized based on the collected six categories of freely accessible chemical databases from literature in this review. RESULTS: Suggestions on how and in which conditions the usage of these databases could be reasonable were provided. Tools and procedures for building 3D structure chemical libraries were also introduced. CONCLUSION: In this review, we described the freely accessible chemical database resources for in silico drug discovery. In particular, the chemical information for building chemical database appears as attractive resources for drug design to alleviate experimental pressure.

20.
J Agric Food Chem ; 66(15): 3773-3782, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29618205

RESUMO

The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa-ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa ( Ki = 0.09 µM) and 4bb ( Ki = 0.02 µM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac ( Ki = 0.54 µM) and flumetsulam ( Ki = 0.38 µM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94-0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds.


Assuntos
Acetolactato Sintase/antagonistas & inibidores , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Herbicidas/química , Proteínas de Plantas/antagonistas & inibidores , Pirimidinas/química , Acetolactato Sintase/química , Arabidopsis/efeitos dos fármacos , Arabidopsis/enzimologia , Compostos de Bifenilo/síntese química , Brassicaceae/efeitos dos fármacos , Brassicaceae/enzimologia , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Herbicidas/síntese química , Herbicidas/farmacologia , Cinética , Proteínas de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Relação Estrutura-Atividade , Controle de Plantas Daninhas
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