Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization

Hao, Ge‐Fei; Yang, Sheng-Gang; Huang, Wei; Wang, Le; Shen, Yanqing; Tu, Wen-Long; Li, Hui; Huang, Li-Shar; Wu, Jiawei; Berry, Edward A.; Yang, Guang‐Fu

doi:10.1038/srep13471

Cited by 18 publications

(17 citation statements)

References 31 publications

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“…Panels A and B represent the side-by-side monomer placement, panel C represents the 90° rotation (one monomer in front of the other). The comparison with the structure of chicken dimeric complex III [pdb: 4U3F 63 ] explains all the projections obtained and corroborates the dimeric oligomeric state of this complex. The absence of additional electronic densities from any projection concurs with the absence of extra atypical subunits.…”

Section: Resultssupporting

confidence: 71%

“…The dimeric complex III was purified by a two-step chromatographic procedure in the presence of β-dodecyl-n-maltoside and analyzed by EM. Overlap of the chicken dimeric complex III (pdb: 4U3F 63 ) over the EM images was performed. ( A – D ) side view projections, ( E – H ) slightly tilted side-view.…”

Section: Resultsmentioning

confidence: 99%

“…However, the lack of QCR8 coding sequence in Euglena nucleotide database 27 questions the complex III biogenesis in Euglena . QCR8, which has one TMH 63 , is required to form an early core subcomplex with COB and QCR7 during complex III biogenesis in S. cerevisiae 62 , 64 . The QCR7 subunit usually shields the quinone pocket of the CYT1 subunit from exposure to the aqueous environment on the matrix side 65 .…”

Section: Resultsmentioning

confidence: 99%

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The atypical subunit composition of respiratory complexes I and IV is associated with original extra structural domains in Euglena gracilis

Miranda-Astudillo

Yadav

Colina‐Tenorio

et al. 2018

Sci Rep

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In mitochondrial oxidative phosphorylation, electron transfer from NADH or succinate to oxygen by a series of large protein complexes in the inner mitochondrial membrane (complexes I–IV) is coupled to the generation of an electrochemical proton gradient, the energy of which is utilized by complex V to generate ATP. In Euglena gracilis, a non-parasitic secondary green alga related to trypanosomes, these respiratory complexes totalize more than 40 Euglenozoa-specific subunits along with about 50 classical subunits described in other eukaryotes. In the present study the Euglena proton-pumping complexes I, III, and IV were purified from isolated mitochondria by a two-steps liquid chromatography approach. Their atypical subunit composition was further resolved and confirmed using a three-steps PAGE analysis coupled to mass spectrometry identification of peptides. The purified complexes were also observed by electron microscopy followed by single-particle analysis. Even if the overall structures of the three oxidases are similar to the structure of canonical enzymes (e.g. from mammals), additional atypical domains were observed in complexes I and IV: an extra domain located at the tip of the peripheral arm of complex I and a “helmet-like” domain on the top of the cytochrome c binding region in complex IV.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The atypical subunit composition of respiratory complexes I and IV is associated with original extra structural domains in Euglena gracilis

Miranda-Astudillo

Yadav

Colina‐Tenorio

et al. 2018

Sci Rep

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“…Finally, the top five new hit candidates selected according to the binding free energy sorting were shown in Figure 3 with the original ligand scaffold (Ligand26) included. It needs to be emphasized that the synthesis of the candidate (Ligand220), the inhibitory kinetics with cytochrome bc 1 complex ( K i = 31.10 nM), and the co-crystal structure study have been completed ( 34 ), which further validated the predicted results of ACFIS.…”

Section: Web Servermentioning

confidence: 78%

ACFIS: a web server for fragment-based drug discovery

Hao¹,

Jiang²,

Ye³

et al. 2016

Nucleic Acids Res

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111

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In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown ‘chemical space’ to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for ‘chemical space’, which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/.

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“…24 , 25 The methoxyacrylate moiety in azoxystrobin is often used as an active group in designing novel fungicides, while the phenoxy moiety is not. 26 − 30 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel 6-Aryloxy-4-chloro-2-phenylpyrimidines as Fungicides and Herbicide Safeners

et al. 2020

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Fenclorim is a commercial herbicide safener with fungicidal activity used for chloroacetanilide herbicides, which might be suitable as a lead compound for screening novel fungicides. However, little has been reported so far on the structure–activity relationship of fungicidal activities of fenclorim or its analogues. Here, a series of 4-chloro-6-substituted phenoxy-2-phenylpyrimidine derivatives was synthesized by a substructure splicing route using fenclorim as a lead compound. The structures of synthesized derivatives were characterized by 1 H NMR, 13 C NMR, and HRMS. Their fungicidal and herbicide safening activities were then evaluated. The results revealed that compound 11 had the best fungicidal activity against Sclerotinia sclerotiorum and Thanatephorus cucumeris , which was better than that of the control pyrimethanil. Moreover, compounds 3 , 5 , and 25 exhibited excellent safening activities against fresh weight, plant height, and root length, respectively. Such activities were significantly improved when compared to fenclorim. In summary, these findings look promising for the preparation of new fungicides and herbicide safeners based on the structure of fenclorim.

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Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization

Cited by 18 publications

References 31 publications

The atypical subunit composition of respiratory complexes I and IV is associated with original extra structural domains in Euglena gracilis

The atypical subunit composition of respiratory complexes I and IV is associated with original extra structural domains in Euglena gracilis

ACFIS: a web server for fragment-based drug discovery

Synthesis of Novel 6-Aryloxy-4-chloro-2-phenylpyrimidines as Fungicides and Herbicide Safeners

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