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Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change. J Comput Aided Mol Des 2006 Mar;20(3):159-78

Date

04/29/2006

Pubmed ID

16645791

DOI

10.1007/s10822-006-9043-5

Abstract

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.

Author List

Sukuru SC, Crepin T, Milev Y, Marsh LC, Hill JB, Anderson RJ, Morris JC, Rohatgi A, O'Mahony G, Grøtli M, Danel F, Page MG, Härtlein M, Cusack S, Kron MA, Kuhn LA

Author

Michael Kron MD Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Aspartate-tRNA Ligase
Brugia malayi
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors
Filaricides
Humans
Ligands
Models, Molecular
Protein Conformation
RNA, Transfer, Amino Acyl
jenkins-FCD Prod-388 89e904233d719332173309c68ab82b0b2a78a3a7