Structure Correlation and Ligand/Receptor Interactions

Klebe, G.

doi:10.1002/9783527616091.ch13

Cited by 16 publications

(15 citation statements)

References 144 publications

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“…It frequently occurs (as adenosine or guanosine monophosphate) as part of cofactors (e.g., NAD, NADP, FAD, ADP, GDP, ATP) bound to protein receptors. Its conformational properties have been studied in detail [2] by comparing structural data from small-molecule crystal structures with those from ligand-enzyme structures determined by protein crystallography.…”

Section: The Program In Operation: a Case Studymentioning

confidence: 99%

“…In order to obtain some evidence for the question put forward on an experimental basis, the geometries of ligands observed in crystal structures of ligand-protein complexes were compared to those obtained from small-molecule crystal structure analyses and computational methods [2]. Crystallographic data are of particular relevance for the present problem, since conformations of molecules adopted in a crystal correspond to geometries exhibited in an anisotropic molecular environment.…”

Section: Introductionmentioning

confidence: 99%

“…In summary, the comparative study [2] of protein and small-molecule data revealed the following conclusions: reliance on just the crystal structures of a ligand itself may not, in most cases, be an infallible and reliable indicator of a biologically active conformation. A similar observation has recently been reported by Ricketts et al [3].…”

Section: Introductionmentioning

confidence: 99%

“…In these cases, the analysis was focused on the study of torsional fragments in the molecules. It was found that the statistical evaluation of conformational preferences of torsional fragments, observed in small-molecule crystal structures, provides important information about conformations relevant at a receptor site [2]. Conformational libraries are obtained that possess some predictive ability to generate relevant binding geometries.…”

Section: Introductionmentioning

confidence: 99%

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A fast and efficient method to generate biologically relevant conformations

Klebe

Mietzner

1994

J Computer-Aided Mol Des

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164

122

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Mutual binding between a ligand of low molecular weight and its macromolecular receptor demands structural complementarity of both species at the recognition site. To predict binding properties of new molecules before synthesis, information about possible conformations of drug molecules at the active site is required, especially if the 3D structure of the receptor is not known. The statistical analysis of small-molecule crystal data allows one to elucidate conformational preferences of molecular fragments and accordingly to compile libraries of putative ligand conformations. A comparison of geometries adopted by corresponding fragments in ligands bound to proteins shows similar distributions in conformations space. We have developed an automatic procedure that generates different conformers of a given ligand. The entire molecule is decomposed into its individual ring and open-chain torsional fragments, each used in a variety of favorable conformations. The latter ones are produced according to the library information about conformational preferences. During this building process, an extensive energy ranking is applied. Conformers ranked as energetically favorable are subjected to an optimization in torsion angle space. During minimization, unfavorable van der Waals interactions are removed while keeping the open-chain torsion angles as close as possible to the experimentally most frequently observed values. In order to assess how well the generated conformers map conformation space, a comparison with experimental data has been performed. This comparison gives some confidence in the efficiency and completeness of this approach. For some ligands that had been structurally characterized by protein crystallography the program was used to generate sets of some 10 to 100 conformers. Among these, geometries are found that fall convincingly close to the conformations actually adopted by these ligands at the binding site.

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Section: The Program In Operation: a Case Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A fast and efficient method to generate biologically relevant conformations

Klebe

Mietzner

1994

J Computer-Aided Mol Des

Self Cite

164

122

View full text Add to dashboard Cite

show abstract

“…Numerous approaches have been taken to this problem ranging from the highly empirical to more rigorous methods, such as free-energy perturbation (FEP) techniques. A detailed discussion is out of the scope of this paper (see also [71]), but it is worth pointing out that a major component in many of the empirical schemes is a measure of the geometric complementarity of the ligand and receptor. This can be expressed as the buried surface area of the ligand [4], [13], [14], or the contact area of the two molecules [83].…”

Section: The Methodsmentioning

confidence: 99%