Abstract
The role of benzodiazepine derivatives (BZD) as a privileged scaffold that mimics β-turn structures (Ripka et al. (1993) Tetrahedron 49:3593–3608) in peptide/protein recognition was reexamined in detail. Stable BZD ring conformers were determined with MM3, and experimental reverse-turn structures were extracted from the basis set of protein crystal structures previously defined by Ripka et al. Ideal β-turns were also modeled and similarly compared with BZD conformers. Huge numbers of conformers were generated by systematically scanning the torsional degrees of freedom for BZDs, as well as those of ideal β-turns for comparison. Using these structures, conformers of BZDs were fit to experimental structures as suggested by Ripka et al., or modeled classical β-turn conformers, and the root-mean-square deviation (RMSD) values were calculated for each pairwise comparison. Pairs of conformers with the smallest RMSD values for overlap of the four α–β side-chain orientations were selected. All overlaps of BZD conformers with experimental β-turns yielded one or more comparisons where the least RMSD was significantly small, 0.48–0.86 Å, as previously suggested. Utilizing a different methodology, the overall conclusion that benzodiazepines could serve as reverse-turn mimetics of Ripka et al. is justified. The least RMSD values for the overlap of BZDs and modeled classical β-turns were also less than 1 Å. When comparing BZDs with experimental or classical β-turns, the set of experimental β-turns selected by Ripka et al. fit the BZD scaffolds better than modeled classical β-turns; however, all the experimental β-turns did not fit a particular BZD scaffold better. A single BZD ring conformation, and/or chiral orientation, can mimic some, but not all, of the experimental β-turn structures. BZD has two central ring conformations and one chiral center that explains why the four variations of the BZD scaffold can mimic all types of β-turn structure examined. It was found, moreover, that the BZD scaffold also mimics each of the nine clusters of experimental orientations of side chains of reverse turns in the Protein Data Bank, when the new classification scheme for the four side-chain directions (the relative orientations of α–β vectors of residues i through i+3) was considered (Tran et al. (2005) J Comput-Aided Mol Des 19:551–566).
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Acknowledgements
The authors thank Dr. Chris M.W. Ho for programming and optimizing the RMSD fitting program. The authors are also grateful to Dr. Jon Våbenø for meaningful discussion of our preliminary results, and Dr. Christina M. Taylor for reviewing the manuscript. Dr. Masayuki Hata was supported by a grant from the Overseas Advanced Educational Research Practice Support Program by The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. Research support from the National Institutes of Health (GM068460) is also acknowledged.
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Hata, M., Marshall, G. Do benzodiazepines mimic reverse-turn structures?. J Comput Aided Mol Des 20, 321–331 (2006). https://doi.org/10.1007/s10822-006-9059-x
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DOI: https://doi.org/10.1007/s10822-006-9059-x