Journal of Computer-Aided Molecular Design

, Volume 20, Issue 3, pp 159–178

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

Authors

  • Sai Chetan K. Sukuru
    • Department of Biochemistry and Molecular BiologyMichigan State University
    • Quantitative Biology and Modeling InitiativeMichigan State University
  • Thibaut Crepin
    • European Molecular Biology Laboratory
  • Youli Milev
    • Department of Medicine and Institute of International HealthMichigan State University
  • Liesl C. Marsh
    • Department of ChemistryUniversity of Canterbury
  • Jonathan B. Hill
    • Department of ChemistryUniversity of Canterbury
  • Regan J. Anderson
    • Department of ChemistryUniversity of Canterbury
  • Jonathan C. Morris
    • School of Chemistry and PhysicsThe University of Adelaide
  • Anjali Rohatgi
    • Department of Biochemistry and Molecular BiologyMichigan State University
  • Gavin O’Mahony
    • Department of ChemistryGöteborg University
  • Morten Grøtli
    • Department of ChemistryGöteborg University
  • Franck Danel
    • Basilea Pharmaceutica Limited
  • Malcolm G. P. Page
    • Basilea Pharmaceutica Limited
  • Michael Härtlein
    • Large Scale Structures GroupInstitute Laue-Langevin
  • Stephen Cusack
    • European Molecular Biology Laboratory
  • Michael A. Kron
    • Department of Biochemistry and Molecular BiologyMichigan State University
    • Department of Biochemistry and Molecular BiologyMichigan State University
    • Quantitative Biology and Modeling InitiativeMichigan State University
Original Paper

DOI: 10.1007/s10822-006-9043-5

Cite this article as:
Sukuru, S.C.K., Crepin, T., Milev, Y. et al. J Comput Aided Mol Des (2006) 20: 159. 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.

Key words

Conformational flexibilityDockingInhibitor designSamplingScoringScreeningAnti-parasitic agentsMSU ProFlexROCKSLIDE

Abbreviations

AARS

aminoacyl-tRNA synthetases

ASNAMS

asparaginyl sulfamoyl adenylate

AsnRS

asparaginyl-tRNA synthetase

CSD

Cambridge Structural Database

LBHAMP

l-aspartate-β-hydroxamate adenylate

MD

molecular dynamics

PDB

Protein Data Bank

SMEVAR

S-methyl-deoxyvariolin B

Copyright information

© Springer Science+Business Media, Inc. 2006