Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping

Yao, Tingting; Fang, Shao‐Wei; Li, Zhongshan; Xiao, Douxin; Cheng, Jing-Li; Huang, Ying; Du, Yong-Jun; Zhao, Jinhao; Dong, Xiaowu

doi:10.1021/acs.jafc.7b00249

Cited by 47 publications

(39 citation statements)

References 41 publications

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“…A successful application of ligand‐based design in crop sciences was demonstrated by Yao et al by targeting an enzyme in plant‐pathogenic fungi . The group performed pharmacophore‐based virtual screening to find inhibitors of succinate dehydrogenase (SDH).…”

Section: Application Case Studiesmentioning

confidence: 99%

Next generation 3D pharmacophore modeling

Schaller

Šribar

Noonan

et al. 2020

WIREs Comput Mol Sci

150

119

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3D pharmacophore models are three‐dimensional ensembles of chemically defined interactions of a ligand in its bioactive conformation. They represent an elegant way to decipher chemically encoded ligand information and have therefore become a valuable tool in drug design. In this review, we provide an overview on the basic concept of this method and summarize key studies for applying 3D pharmacophore models in virtual screening and mechanistic studies for protein functionality. Moreover, we discuss recent developments in the field. The combination of 3D pharmacophore models with molecular dynamics simulations could be a quantum leap forward since these approaches consider macromolecule–ligand interactions as dynamic and therefore show a physiologically relevant interaction pattern. Other trends include the efficient usage of 3D pharmacophore information in machine learning and artificial intelligence applications or freely accessible web servers for 3D pharmacophore modeling. The recent developments show that 3D pharmacophore modeling is a vibrant field with various applications in drug discovery and beyond. This article is categorized under: Computer and Information Science > Chemoinformatics Computer and Information Science > Computer Algorithms and Programming Molecular and Statistical Mechanics > Molecular Interactions

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Section: Application Case Studiesmentioning

confidence: 99%

Next generation 3D pharmacophore modeling

Schaller

Šribar

Noonan

et al. 2020

WIREs Comput Mol Sci

150

119

View full text Add to dashboard Cite

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“…In recent years, the combination of computer aided drug design (CADD) and experimental high throughput screening (HTS) has become an effective method in lead compounds discovery and development. [16][17][18] One common used approach in CADD is structure-based virtual screening, which enables docking of numerous compounds into a certain biomolecular target and then evaluates in a speedy and inexpensive manner. Moreover, this molecular docking can also be used to view the binding modes between compounds and target, even further analyze the possible mechanisms.…”

Section: -4mentioning

confidence: 99%

Discovery of novel inhibitors of RNA silencing suppressor P19 based on virtual screening

Lei

Deng

et al. 2018

RSC Adv.

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To control plant viruses, viral RNA silencing suppressors are important drug targets due to their key roles in interfering antiviral RNA silencing. Here we have presented a strategy, combining virtual and experimental screening, to discover the inhibitors of viral suppressor. By docking 157 026 compounds from a natural product library into P19 model, eighteen candidate compounds were selected. Candidates VS2, VS12, VS14 and VS15 displayed strong binding ability to P19 in the surface plasmon resonance imaging assay with K D values of 136.2, 111.6, 81.2 and 124.5 nM, respectively. Then the inhibition activities of these inhibitors on the association between P19 and siRNA were also affirmed by electrophoretic mobility shift assay. Moreover, the antiviral effects on plants showed that compounds VS14 and VS15 both exhibited antiviral activities against Tomato bushy stunt virus (TBSV) in vivo with inhibition rates of 32.35% and 16.61% in 11 dpi, respectively. This strategy would be a powerful tool for the discovery of novel antiviral agents and provide new insights into the control of plant viruses.

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“…Most current SDHI compounds have similar structures of amide bridge (Fig. 1(a)), which results in the single binding mode with SDH, 16–20 and consequently causes resistance issues 21,22 . Moreover, the lack of activity against oomycetes led to current bottleneck of SDHI fungicides 15 .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antifungal/anti‐oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors

Wang

Chen

et al. 2021

Pest Management Science

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BACKGROUND Succinate dehydrogenase inhibitors (SDHIs) play an increasingly important role in controlling plant diseases. However, the similar structures of SDHIs result in rapid development of cross‐resistance development and a clear bottleneck of poor activity against oomycetes, therefore the need to seek new SDHI fungicides with novel structures is urgent. RESULTS Innovative pyrazolyl oxime ethers were designed by replacing amide with oxime ether based on the succinate dehydrogenase (SDH) structure, and 19 pairs of Z‐ and E‐isomers were efficiently prepared for the discovery of SDHI compounds with a novel bridge. Their biological activities against four fungi and two oomycetes were evaluated, and substantial differences were observed between the Z‐ and E‐ isomers of the title compounds. Furthermore, most of these compounds exhibited remarkable activities against Rhizoctonia solani with EC50 values of less than 10 mg L−1 in vitro, and bioassay in vivo further confirmed that E‐I‐6 exhibited good protective efficacy (76.12%) at 200 mg L−1. In addition, Z‐I‐12 provided better activity against the oomycetes Pythium aphanidermatum and Phytophthora capsici (EC50 = 1.56 and 0.93 mg L−1) than those of boscalid. Moreover, E‐I‐12 exhibited excellent SDH inhibition (IC50 = 0.21 mg L−1) thanks to its good binding ability to the SDH by hydrogen‐bonding interactions, π‐cation interaction and hydrophobic interactions. CONCLUSION Novel pyrazolyl oxime ethers have the potential as SDHI compounds for future development, and the strategy of replacing an amide bond with oxime ether may offer an alternative option in SDHI fungicide discovery.

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Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping

Cited by 47 publications

References 41 publications

Next generation 3D pharmacophore modeling

Next generation 3D pharmacophore modeling

Discovery of novel inhibitors of RNA silencing suppressor P19 based on virtual screening

Design, synthesis and antifungal/anti‐oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors

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