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The use of molecular dynamics simulations to evaluate the DNA sequence-selectivity of G-A cross-linking PBD-duocarmycin dimers.
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Jan2017, Vol. 27 Issue 1, p102-108. 7p. - Publication Year :
- 2017
-
Abstract
- The pyrrolobenzodiazepine (PBD) and duocarmycin families are DNA-interactive agents that covalently bond to guanine (G) and adenine (A) bases, respectively, and that have been joined together to create synthetic dimers capable of cross-linking G-G, A-A, and G-A bases. Three G-A alkylating dimers have been reported in publications to date, with defined DNA-binding sites proposed for two of them. In this study we have used molecular dynamics simulations to elucidate preferred DNA-binding sites for the three published molecular types. For the PBD-CPI dimer UTA-6026 (1), our simulations correctly predicted its favoured binding site (i.e., 50-C(G)AATTA-30) as identified by DNA cleavage studies. However, for the PBD-CI molecule ('Compound 11', 3), we were unable to reconcile the results of our simulations with the reported preferred cross-linking sequence (50-ATTTTCC(G)-30). We found that the molecule is too short to span the five base pairs between the A and G bases as claimed, but should target instead a sequence such as 50-ATTTC(G)-30 with two less base pairs between the reacting G and A residues. Our simulation results for this hybrid dimer are also in accord with the very low interstrand cross-linking and in vitro cytotoxicity activities reported for it. Although a preferred cross-linking sequence was not reported for the third hybrid dimer ('27eS', 2), our simulations predict that it should span two base pairs between covalently reacting G and A bases (e.g., 50-GTAT(A)-30). [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 27
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 119962150
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.10.022