Biomedical subjects

Allister J Maynard

Publications and source records attributed to Allister J Maynard.

2 recordsLinked to original sources

PubMed2003

DNA recognition by the anthracycline antibiotic respinomycin D: NMR structure of the intercalation complex with d(AGACGTCT)2.

Respinomycin D is a member of the anthracycline family of antitumour antibiotics that interact with double stranded DNA through intercalation. The clinical agents daunomycin and doxorubicin are the most well-studied of this class but have a relatively simple molecular architecture in which the pendant daunosamine sugar resides in the DNA minor groove. Respinomycin D, which belongs to the nogalamycin group of anthracyclines, possesses additional sugar residues at either end of the aglycone chromophore that modulate the biological activity but whose role in molecular recognition is unknown. We report the NMR structure of the respinomycin D-d(AGACGTCT)2 complex in solution derived from NOE restraints and molecular dynamics simulations. We show that the drug threads through the DNA double helix forming stabilising interactions in both the major and minor groove, the latter through a different binding geometry to that previously reported. The bicycloaminoglucose sugar resides in the major groove and makes specific contacts with guanine at the 5'-CpG intercalation site, however, the disaccharide attached at the C4 position plays little part in drug binding and DNA recognition and is largely solvent exposed.

Anthracyclines↗

PubMedDate not supplied

Using pharmacophore models to gain insight into structural binding and virtual screening: an application study with CDK2 and human DHFR.

This study provides results from two case studies involving the application of the HypoGenRefine algorithm within Catalyst for the automated generation of excluded volume from ligand information alone. A limitation of pharmacophore feature hypothesis alone is that activity prediction is based purely on the presence and arrangement of pharmacophoric features; steric effects remained unaccounted. Recently reported studies have illustrated the usefulness of combining excluded volumes to the pharmacophore models. In general, these excluded volumes attempt to penalize molecules occupying steric regions that are not occupied by active molecules. The HypoGenRefine algorithm in Catalyst accounts for steric effects on activity, based on the targeted addition of excluded volume features to the pharmacophores. The automated inclusion of excluded volumes to pharmacophore models has been applied to two systems: CDK2 and human DHFR. These studies are used as examples to illustrate how ligands could bind in the protein active site with respect to allowed and disallowed binding regions. Additionally, automated refinement of the pharmacophore with these excluded volume features provides a more selective model to reduce false positives and a better enrichment rate in virtual screening.

Algorithms↗