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Cited by 447

The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.

Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding

Perola, Emanuele, Charifson, Paul S.·2004·Journal of Medicinal Chemistry
DOI 10.1021/jm030563w
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Abstract

This paper describes a large-scale study on the nature and the energetics of the conformational changes drug-like molecules experience upon binding. Ligand strain energies and conformational reorganization were analyzed with different computational methods on 150 crystal structures of pharmaceutically relevant protein-ligand complexes. The common knowledge that ligands rarely bind in their lowest calculated energy conformation was confirmed. Additionally, we found that over 60% of the ligands do not bind in a local minimum conformation. While approximately 60% of the ligands were calculated to bind with strain energies lower than 5 kcal/mol, strain energies over 9 kcal/mol were calculated in at least 10% of the cases regardless of the method used. A clear correlation was found between acceptable strain energy and ligand flexibility, while there was no correlation between strain energy and binding affinity, thus indicating that expensive conformational rearrangements can be tolerated in some cases without overly penalizing the tightness of binding. On the basis of the trends observed, thresholds for the acceptable strain energies of bioactive conformations were defined with consideration of the impact of ligand flexibility. An analysis of the degree of folding of the bound ligands confirmed the general tendency of small molecules to bind in an extended conformation. The results suggest that the unfolding of hydrophobic ligands during binding, which exposes hydrophobic surfaces to contact with protein residues, could be one of the factors accounting for high reorganization energies. Finally, different methods for conformational analysis were evaluated, and guidelines were defined to maximize the prevalence of bioactive conformations in computationally generated ensembles.

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Metadata

Authors
Perola, E., & Charifson, P. S.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2004-04-07
Volume
47
Issue
10
Pages
2499-2510
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm030563w
OpenAlex
W2077467665
Cited by
447
References
22
FWCI
25.85
Type
journal article
Language
en
Open access
closed

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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