期刊
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
卷 25, 期 1, 页码 1-12出版社
SPRINGER
DOI: 10.1007/s10822-010-9397-6
关键词
X-ray crystallography; Ligand design; Molecular dynamics simulations; Free energy calculations; Binding mode
资金
- NCI National Facility [m72, n63]
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.
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