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Journal of Computer-Aided Molecular Design

, Volume 20, Issue 3, pp 159–178 | Cite as

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

  • Sai Chetan K. Sukuru
  • Thibaut Crepin
  • Youli Milev
  • Liesl C. Marsh
  • Jonathan B. Hill
  • Regan J. Anderson
  • Jonathan C. Morris
  • Anjali Rohatgi
  • Gavin O’Mahony
  • Morten Grøtli
  • Franck Danel
  • Malcolm G. P. Page
  • Michael Härtlein
  • Stephen Cusack
  • Michael A. Kron
  • Leslie A. Kuhn
Original Paper

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 flexibility Docking Inhibitor design Sampling Scoring Screening Anti-parasitic agents MSU ProFlex ROCK SLIDE 

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

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Notes

Acknowledgements

We thank Dr. Paul Sanschagrin for his initial CSD screening that identified variolin B as an inhibitor, and Dr. Maria Zavodszky for her assistance with ROCK. We also thank NCI for providing us with samples of plated compounds and Dr. Samuel Danishefsky for providing us with rishirilide B. Drs. Holger Gohlke and Gerhard Klebe, Dr. Shaomeng Wang, and OpenEye Scientific Software (Santa Fe, NM) generously provided their DrugScore, X-Score, and Omega software for our use. This work was supported by NIH grants GM 67249 to L.A.K. and U01 AI53877 to M.A.K., S.C., M.G.P.P., F.D., and L.A.K.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Sai Chetan K. Sukuru
    • 1
    • 2
  • Thibaut Crepin
    • 4
  • Youli Milev
    • 3
  • Liesl C. Marsh
    • 5
  • Jonathan B. Hill
    • 5
  • Regan J. Anderson
    • 5
  • Jonathan C. Morris
    • 6
  • Anjali Rohatgi
    • 1
  • Gavin O’Mahony
    • 7
  • Morten Grøtli
    • 7
  • Franck Danel
    • 8
  • Malcolm G. P. Page
    • 8
  • Michael Härtlein
    • 9
  • Stephen Cusack
    • 4
  • Michael A. Kron
    • 1
  • Leslie A. Kuhn
    • 1
    • 2
  1. 1.Department of Biochemistry and Molecular BiologyMichigan State UniversityEast LansingUSA
  2. 2.Quantitative Biology and Modeling InitiativeMichigan State UniversityEast LansingUSA
  3. 3.Department of Medicine and Institute of International HealthMichigan State UniversityEast LansingUSA
  4. 4.European Molecular Biology LaboratoryGrenobleFrance
  5. 5.Department of ChemistryUniversity of CanterburyChristchurchNew Zealand
  6. 6.School of Chemistry and PhysicsThe University of AdelaideAdelaideAustralia
  7. 7.Department of ChemistryGöteborg UniversityGöteborgSweden
  8. 8.Basilea Pharmaceutica LimitedBaselSwitzerland
  9. 9.Large Scale Structures GroupInstitute Laue-LangevinGrenobleFrance

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