newsletter #13 — literature corner

We will be making a regular point of providing you with the latest publications, reports and papers including developments and products from BioSolveIT and its associated owners.

Discovery and optimization of novel, non-steroidal glucocorticoid receptor modulators
Nicholas C. Ray, Robin D. Clark, David E. Clark, Karen Williams, H.G. Hickin, Peter H. Crackett, Hazel J. Dyke, Peter M. Lockey, Melanie Wong, René Devos, Anne White, and Joseph K. Belanoff.
Bioorg. Med. Chem. Lett., 17, (17), 4901-4905, (2007)

The paper describes a virtual screening approach which uses FlexS for 3D similarity searching for novel glucocorticoid receptor antagonists. A focused library of 862 compounds was created using known antagonists as a guide, and then performing clustering and pre-filtering of a 718,000 compound library. 123 initial hits were obtained with FlexS's flexible superposition search using 4 query compounds (containing two enantiomers). Refinement of these hits was undertaken by removing duplicates and considering supplier reliability. Thus, 18 compounds were tested in binding assays providing a hit with a Ki of 4.5 µM, further screening with this compound lead to a hit with a Ki value of 16 nM for a binding assay and 135 nM for a functional assay.
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GPCR Structure-Based Virtual Screening Approach for CB2 Antagonist Search
Jian-Zhong Chen, Junmei Wang and Xiang-Qun Xie
J. Chem. Inf. Model., 47 (4), 1626 -1637, (2007)

The paper discusses the use of FlexX-Pharm docking with a homology model of CB2 (cannabinoid receptor) to identify known antagonists from a test compound database of molecules. A homology model of CB2 was built using bovine rhodopsin, a MD/MM approach and mutagenesis data. A consensus scoring method with FlexX-Pharm docking was employed to find all known antagonists with good enrichment from a significant amount of randomly chosen molecules. The study demonstrates the value and success obtainable whilst using highly refined homology models in docking studies.
Link to article

ReCore: A Fast and Versatile Method for Scaffold Hopping Based on Small Molecule Crystal Structure Conformations
Patrick Maass, Tanja Schulz-Gasch, Martin Stahl and Matthias Rarey
J. Chem. Inf. Model., 47 (2), 390 -399, (2007)

ReCore replaces central elements of known active structures to permit scaffold hopping into new chemical space. It enables exploration of large search spaces whilst avoiding structures with strained conformations in a quick interactive manner. A geometrical rank searching procedure is used with the ligand conformational crystal structure to identify compatible 3D fragments. Exit bond vector cuts are selected to define a core fragment for replacement. Additional pharmacophoric prioritization can be used to find fragments fulfilling all the applied constraints with results ordered by increasing deviation from the query constraints. The method was shown to propose new valid scaffold topologies for three different drug design scenarios.
Link to article

Supervised Scoring Models with Docked Ligand Conformations for Structure-Based Virtual Screening
Reiji Teramoto and Hiroaki Fukunishi
J. Chem. Inf. Model., 47 (5), 1858 -1867, (2007)

This paper proposes supervised scoring models (SSM) for efficient tailored scoring for specific protein targets. The SSM employ a rough linear correlation between binding free energy and the root mean square deviation of a native ligand for predicting binding energy. The SSM was applied to the FlexX scoring function for five different target proteins with the SSM enhancing scoring in all five cases. The SSM was shown to be particularly useful for practical drug screening as good enhancement of enrichments occurred in the top ranks of screened compounds.
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