Discovery of a potent and selective series of pyrazole bacterial methionyl-tRNA synthetase inhibitors

Finn, John M.; Mattia, Karen M.; Morytko, Mike; Ram, Siya; Yang, Yingfei; Wu, Ximao; Mak, Elsa; Gallant, Paul; Keith, Dennis D.

doi:10.1016/s0960-894x(03)00298-1

Cited by 69 publications

(15 citation statements)

References 13 publications

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“…Lee and Kim used comparative molecular field analysis [81] to dock four known inhibitors of S. aureus MetRS and develop a predictive quantitative structureactivity relationship [82]. Most of the highly potent and selective AARS inhibitors discovered in recent years have come from in vitro screening and optimization studies [83][84][85][86]. Here we show that structure-based screening against an AARS target can identify several new classes of inhibitors.…”

Section: Discussionmentioning

confidence: 87%

Discovering New Classes of Brugia malayi Asparaginyl-tRNA Synthetase Inhibitors and Relating Specificity to Conformational Change

Sukuru

Crépin

Milev

et al. 2006

J Comput Aided Mol Des

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SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.

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Section: Discussionmentioning

confidence: 87%

Discovering New Classes of Brugia malayi Asparaginyl-tRNA Synthetase Inhibitors and Relating Specificity to Conformational Change

Sukuru

Crépin

Milev

et al. 2006

J Comput Aided Mol Des

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“…1 -(4-Trifluoromethoxy)-phenyl pyrazoles (25,26) Trifluoromethoxy benzimidazole 37 containing a chloromethyi group in the 2-position was synthesized through acid catalized condensation of 4-trifluoromethoxyortho-phenylene diamine 36 with chloroacetic acid (29). Compound 37 was used as an efficient alkylating agent for the preparation of pharmacologically active derivatives of pyperazine (Scheme 12).…”

Section: Azolesmentioning

confidence: 99%

Trifluoromethoxy Containing Azoles and Azines: Synthesis and Biological Activity

Вовк

Pinchuk

Sukach

et al. 2009

ACS Symposium Series

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“…1-29) was used to generate HypoGen hypotheses by considering structural diversity and wide coverage of activity range [16][17][18][19][20]. Conformationally restricted analogues of the central linker unit of S. aureus MetRS inhibitors [18] have been included in the training set.…”

Section: Training Set Selection and Conformational Generationmentioning

confidence: 99%

Pharmacophore identification and virtual screening for methionyl-tRNA synthetase inhibitors

Bharatham

Lee

2007

Journal of Molecular Graphics and Modelling

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Discovery of a potent and selective series of pyrazole bacterial methionyl-tRNA synthetase inhibitors

Cited by 69 publications

References 13 publications

Discovering New Classes of Brugia malayi Asparaginyl-tRNA Synthetase Inhibitors and Relating Specificity to Conformational Change

Discovering New Classes of Brugia malayi Asparaginyl-tRNA Synthetase Inhibitors and Relating Specificity to Conformational Change

Trifluoromethoxy Containing Azoles and Azines: Synthesis and Biological Activity

Pharmacophore identification and virtual screening for methionyl-tRNA synthetase inhibitors

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