Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes

Malde, AK and Mark, AE (2011) Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes. Journal of Computer-Aided Molecular Design, 25 1: 1-12. doi:10.1007/s10822-010-9397-6


Author Malde, AK
Mark, AE
Title Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes
Journal name Journal of Computer-Aided Molecular Design   Check publisher's open access policy
ISSN 0920-654X
1573-4951
Publication date 2011-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1007/s10822-010-9397-6
Open Access Status
Volume 25
Issue 1
Start page 1
End page 12
Total pages 12
Place of publication Dordrecht, Netherlands
Publisher Springer Netherlands
Language eng
Abstract Despite its central role in structure based drug design the determination of the binding mode (position, orientation and conformation in addition to protonation and tautomeric states) of small heteromolecular ligands in protein:ligand complexes based on medium resolution X-ray diffraction data is highly challenging. In this perspective we demonstrate how a combination of molecular dynamics simulations and free energy (FE) calculations can be used to correct and identify thermodynamically stable binding modes of ligands in X-ray crystal complexes. The consequences of inappropriate ligand structure, force field and the absence of electrostatics during X-ray refinement are highlighted. The implications of such uncertainties and errors for the validation of virtual screening and fragment-based drug design based on high throughput X-ray crystallography are discussed with possible solutions and guidelines. © Springer
Keyword X-ray crystallography
Ligand design
Molecular dynamics simulations
Free energy calculations
Binding mode
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID m72
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 04 Mar 2011, 21:48:34 EST by Professor Alan Mark on behalf of School of Chemistry & Molecular Biosciences