ArticleJournal of computer-aided molecular design2011
Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes.
Article in Journal of computer-aided molecular design, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed.
- Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations.Journal of computer-aided molecular design · 2023Article
- High-throughput quantum-mechanics/molecular-mechanics (ONIOM) macromolecular crystallographic refinement with PHENIX/DivCon: the impact of mixed Hamiltonian methods on ligand and protein structure.Acta crystallographica. Section D, Structural biology · 2018Article
- Assigning crystallographic electron densities with free energy calculations-The case of the fluoride channel Fluc.PloS one · 2018Article
- Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding.Journal of molecular recognition : JMR · 2017Review
- Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop.Structure (London, England : 1993) · 2016Article
- XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement.Acta crystallographica. Section D, Structural biology · 2016Article
- The future of crystallography in drug discovery.Expert opinion on drug discovery · 2014Review
- The quality and validation of structures from structural genomics.Methods in molecular biology (Clifton, N.J.) · 2014Article
- Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II.Scientific reports · 2013Article
- Fragment-based screening by protein crystallography: successes and pitfalls.International journal of molecular sciences · 2012Review
- Missing fragments: detecting cooperative binding in fragment-based drug design.ACS medicinal chemistry letters · 2012Article
- PDB ligand conformational energies calculated quantum-mechanically.Journal of chemical information and modeling · 2012Article
- X-ray crystallography: Assessment and validation of protein-small molecule complexes for drug discovery.Expert opinion on drug discovery · 2011Article
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2 authors.
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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.
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