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Discovering new cla...
Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.
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Sukuru, Sai Chetan K (author)
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Crepin, Thibaut (author)
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Milev, Youli (author)
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Marsh, Liesl C (author)
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Hill, Jonathan B (author)
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Anderson, Regan J (author)
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Morris, Jonathan C (author)
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Rohatgi, Anjali (author)
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O'Mahony, Gavin (author)
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- Grøtli, Morten, 1966 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
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Danel, Franck (author)
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Page, Malcolm G P (author)
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Härtlein, Michael (author)
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Cusack, Stephen (author)
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Kron, Michael A (author)
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Kuhn, Leslie A (author)
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(creator_code:org_t)
- 2006-04-28
- 2006
- English.
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In: Journal of computer-aided molecular design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 20:3, s. 159-78
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https://doi.org/10.1...
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Animals
- Aspartate-tRNA Ligase
- antagonists & inhibitors
- chemistry
- Brugia malayi
- enzymology
- Crystallography
- X-Ray
- Drug Design
- Enzyme Inhibitors
- chemistry
- classification
- Filaricides
- chemistry
- Humans
- Ligands
- Models
- Molecular
- Protein Conformation
- RNA
- Transfer
- Amino Acyl
- antagonists & inhibitors
- chemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sukuru, Sai Chet ...
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Crepin, Thibaut
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Milev, Youli
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Marsh, Liesl C
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Hill, Jonathan B
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Anderson, Regan ...
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show more...
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Morris, Jonathan ...
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Rohatgi, Anjali
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O'Mahony, Gavin
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Grøtli, Morten, ...
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Danel, Franck
-
Page, Malcolm G ...
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Härtlein, Michae ...
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Cusack, Stephen
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Kron, Michael A
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Kuhn, Leslie A
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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University of Gothenburg