newsletter 17 – 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.

Fragment Shuffling: An Automated Workflow for Three-Dimensional Fragment-Based Ligand Design
Britta Nisius and Ulrich Rester
J. Chem. Inf. Model., 2009, 49 (5), pp 1211-1222

The paper presents a fragment shuffling based method that utilizes 3D ligand data, FlexX as a means of scoring, an incremental construction with a greedy search algorithm guided by the calculated fragment scores. Validation work on the method is presented on kinase data and compared to the BREED technique. Additionally, a prospective study for the design of novel non-peptidic thrombin inhibitors is also provided.
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A Structure-Based Approach to Ligand Discovery for 2C-Methyl-d-erythritol-2,4-cyclodiphosphate Synthase: A Target for Antimicrobial Therapy
Nicola L. Ramsden, Lori Buetow, Alice Dawson, Lauris A. Kemp, Venkatsubramanian Ulaganathan, Ruth Brenk, Gerhard Klebe, and William N. Hunter
J. Med. Chem., 2009, 52 (8), pp 2531-2542

The paper describes a combination of FlexX and a hierarchical filtering methodology and to generate hits of which 10 were then verified with X-ray crystallography and a surface plasmon resonance assay. Two molecules were identified as weak binders and one of the putative Zn2+-binding compounds was developed to give the lowest measured KD to date (1.92 (0.18 µM)). The work provides a platform for the further development of IspF inhibitors to generate compounds of true therapeutic potential against microbial pathogens.
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Bioisosteric Similarity of Molecules Based on Structural Alignment and Observed Chemical Replacements in Drugs
Markus Krier and Michael C. Hutter
J. Chem. Inf. Model., 2009, 49 (5), pp 1280-1297

The authors report the usage of FTrees-online to help provide a means of comparison for their new method to perform a bioisosteric similarity. This bioisosteric similarity calculated measure was used to perform virtual screening in several publicly available substance databases. Compounds obtained at the highest rank from the ZINC lead-like subset library showed distinct differences in comparison to compounds selected with FTrees, however there were also apparent similarities of the results obtained.
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