ReviewJournal of molecular recognition : JMR2017
Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding.
Review in Journal of molecular recognition : JMR, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Assessing conformation validity and rationality of deep learning-generated 3D molecules.Nature communications · 2026Article
- Discriminating High from Low Energy Conformers of Druglike Molecules: An Assessment of Machine Learning Potentials and Quantum Chemical Methods.Chemphyschem : a European journal of chemical physics and physical chemistry · 2025Article
- Virtual screening: hope, hype, and the fine line in between.Expert opinion on drug discovery · 2025Review
- An ANI-2 enabled open-source protocol to estimate ligand strain after docking.Journal of computational chemistry · 2025Article
- Applying atomistic neural networks to bias conformer ensembles towards bioactive-like conformations.Journal of cheminformatics · 2023Article
- 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
- Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads.Journal of medicinal chemistry · 2023Article
- Collaborative Assessment of Molecular Geometries and Energies from the Open Force Field.Journal of chemical information and modeling · 2022Article
- An Efficient Approach to Large-Scale Ab Initio Conformational Energy Profiles of Small Molecules.Molecules (Basel, Switzerland) · 2022Article
- Computational design of a sensitive, selective phase-changing sensor protein for the VX nerve agent.Science advances · 2022Article
- Increased Molecular Flexibility Widens the Gap betweenACS medicinal chemistry letters · 2022Article
- Ligand Strain Energy in Large Library Docking.Journal of chemical information and modeling · 2021Article
- Macromolecular refinement of X-ray and cryoelectron microscopy structures with Phenix/OPLS3e for improved structure and ligand quality.Structure (London, England : 1993) · 2021Article
- Conformational analysis of macrocycles: comparing general and specialized methods.Journal of computer-aided molecular design · 2020Article
- Fast, efficient fragment-based coordinate generation for Open Babel.Journal of cheminformatics · 2019Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
In this review, we address a fundamental question: What is the range of conformational energies seen in ligands in protein-ligand crystal structures? This value is important biophysically, for better understanding the protein-ligand binding process; and practically, for providing a parameter to be used in many computational drug design methods such as docking and pharmacophore searches. We synthesize a selection of previously reported conflicting results from computational studies of this issue and conclude that high ligand conformational energies really are present in some crystal structures. The main source of disagreement between different analyses appears to be due to divergent treatments of electrostatics and solvation. At the same time, however, for many ligands, a high conformational energy is in error, due to either crystal structure inaccuracies or incorrect determination of the reference state. Aside from simple chemistry mistakes, we argue that crystal structure error may mainly be because of the heuristic weighting of ligand stereochemical restraints relative to the fit of the structure to the electron density. This problem cannot be fixed with improvements to electron density fitting or with simple ligand geometry checks, though better metrics are needed for evaluating ligand and binding site chemistry in addition to geometry during structure refinement. The ultimate solution for accurately determining ligand conformational energies lies in ultrahigh-resolution crystal structures that can be refined without restraints.
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Registered trials
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