Morten Dahl Sørensen

SHOP: receptor-based scaffold HOPping by GRID-based similarity searches.

A new field-derived 3D method for receptor-based scaffold hopping, implemented in the software SHOP, is presented. Information from a protein-ligand complex is utilized to substitute a fragment of the ligand with another fragment from a database of synthetically accessible scaffolds. A GRID-based interaction profile of the receptor and geometrical descriptions of a ligand scaffold are used to obtain new scaffolds with different structural features and are able to replace the original scaffold in the protein-ligand complex. An enrichment study was successfully performed verifying the ability of SHOP to find known active CDK2 scaffolds in a database. Additionally, SHOP was used for suggesting new inhibitors of p38 MAP kinase. Four p38 complexes were used to perform six scaffold searches. Several new scaffolds were suggested, and the resulting compounds were successfully docked into the query proteins.

Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer.

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

17S, 20S-Methanofusidic acid, a new potent semi-synthetic fusidane antibiotic

A novel fusidic acid type antibiotic having the side chain linked to the tetracyclic ring system via a spiro-cyclopropane system is described. 17S,20S-Methanofusidic acid is obtained by an efficient synthetic route including cyclopropanation of the Delta17(20) bond with attack solely from the least hindered alpha-face. The spiro-cyclopropane system orients the side chain into a bioactive conformational space. The new 17S,20S-methanofusidic acid exerts antibacterial activity against several Gram-positive species with potency essentially equal to natural fusidic acid.

Binding of alpha-hydroxy-beta-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions.

The binding mode of a recently described set of α-hydroxy-β-amino acid inhibitors of methionine aminopeptidase type 2 is suggested in the present work. The binding mode is supported by analysis of published structures of transition state analogues co-crystallised with E. coli methionine aminopeptidase and by a comparison of molecular interaction fields calculated using GRID for E. coli and human methionine aminopeptidase. Based on the suggested binding mode two types of scoring functions have been evaluated and compared. These are the commercially available consensus score, CScore, and scoring of the ligands employing energies calculated using the Merck Molecular Force Field (MMFF). Enriched subsets of ligands were obtained when using CScore, but these scores could not be used to assess the relative affinities of individual compounds. Although still not sufficiently accurate for reliable predictive purposes, an improved correlation was obtained between structure and affinity using a combined force field energy including contributions from solvation and conformational energy penalty for binding.