Abstract:
:To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Nervall M,Hanspers P,Carlsson J,Boukharta L,Aqvist Jdoi
10.1021/jm701218jsubject
Has Abstractpub_date
2008-05-08 00:00:00pages
2657-67issue
9eissn
0022-2623issn
1520-4804journal_volume
51pub_type
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