Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.

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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Läkemedelskemi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medicinal Chemistry hsv//eng
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

Crepin, Thibaut (author)
Milev, Youli (author)
Marsh, Liesl C (author)
Hill, Jonathan B (author)
Anderson, Regan J (author)
Morris, Jonathan C (author)
Rohatgi, Anjali (author)
O'Mahony, Gavin (author)
Grøtli, Morten,1966Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry(Swepub:gu)xgromo (author)
Danel, Franck (author)
Page, Malcolm G P (author)
Härtlein, Michael (author)
Cusack, Stephen (author)
Kron, Michael A (author)
Kuhn, Leslie A (author)
Göteborgs universitetInstitutionen för kemi (creator_code:org_t)

In:Journal of computer-aided molecular design: Springer Science and Business Media LLC20:3, s. 159-780920-654X1573-4951

By the author/editor: Sukuru, Sai Chet ...; Crepin, Thibaut; Milev, Youli; Marsh, Liesl C; Hill, Jonathan B; Anderson, Regan ...; show more...; Morris, Jonathan ...; Rohatgi, Anjali; O'Mahony, Gavin; Grøtli, Morten, ...; Danel, Franck; Page, Malcolm G ...; Härtlein, Michae ...; Cusack, Stephen; Kron, Michael A; Kuhn, Leslie A; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

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