Skip navigation

Computational studies support the role of the C7-sibirosamine sugar of the pyrrolobenzodiazepine (PBD) sibiromycin in transcription factor inhibition

Computational studies support the role of the C7-sibirosamine sugar of the pyrrolobenzodiazepine (PBD) sibiromycin in transcription factor inhibition

Jackson, Paul J. M., James, Colin H., Jenkins, Terence C., Rahman, Khondaker C. and Thurston, David E. (2014) Computational studies support the role of the C7-sibirosamine sugar of the pyrrolobenzodiazepine (PBD) sibiromycin in transcription factor inhibition. ACS Chemical Biology, 9 (10). pp. 2432-2440. ISSN 1554-8929 (Print), 1554-8937 (Online) (doi:https://doi.org/10.1021/cb5002203)

Full text not available from this repository.

Abstract

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of sequence-selective, DNA minor-groove binding agents that covalently attach to guanine residues. Originally derived from Streptomyces species, a number of naturally occurring PBD monomers exist with varying A-Ring and C2-substituents. One such agent, sibiromycin, is unusual in having a glycosyl residue (sibirosamine) at its A-Ring C7-position. It is the most cytotoxic member of the naturally occurring PBD family and has the highest DNA-binding affinity. Recently, the analogue 9-deoxysibiromyin was produced biosynthetically by Yonemoto and co-workers.1 Differing only in the loss of the A-Ring C9-hydroxyl group, it was reported to have a significantly higher DNA-binding affinity than sibiromycin based on DNA thermal denaturation studies, although these data have since been retracted.2 As deletion of the C9-OH moiety, which points toward the DNA minor groove floor, might intuitively be expected to reduce DNA-binding affinity through the loss of hydrogen bonding, we carried out molecular dynamics simulations on the interaction of both molecules with DNA over a 10 ns time-course in explicit solvent. Our results suggest that the two molecules may differ in their sequence-selectivity and that 9-deoxysibiromycin should have a lower binding affinity for certain sequences of DNA compared to sibiromycin. Our molecular dynamics results indicate that the C7-sibirosamine sugar does not form hydrogen bonding interactions with groups in the DNA minor-groove wall as previously reported, but instead points orthogonally out from the minor groove where it may inhibit the approach of DNA control proteins such as transcription factors. This was confirmed through a docking study involving sibiromycin and the GAL4 transcription factor, and these results could explain the significantly enhanced cytotoxicity of sibiromycin compared to other PBD family members without bulky C7-substituents.

Item Type: Article
Uncontrolled Keywords: computational studies support, C7-sibirosamine sugar, pyrrolobenzodiazepine (PBD) sibiromycin, transcription factor inhibition
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Faculty / Department / Research Group: Faculty of Engineering & Science
Related URLs:
Last Modified: 14 Oct 2016 09:29
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
URI: http://gala.gre.ac.uk/id/eprint/12469

Actions (login required)

View Item View Item