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High-throughput screening campaigns are fuelled not only by corporate or "maximally diverse" compound collections, but increasingly accompanied by target- or bioactivity-focused selections of screening compounds. Computer-assisted library design methods aid in the compilation of focused molecule libraries. A prerequisite for application of any such computational approach is the definition of a reference set and a molecular similarity metric, based on which compound clustering and iterative virtual screening are performed. In this context the self-organizing map (SOM, Kohonen network) and variations thereof have found widespread application. SOMs cover such diverse fields of drug discovery as screening library design, scaffold-hopping, and repurposing. Here we present the concept of the SOM technique along with recent case studies. Advantages, limitations and potential future applications are critically discussed.

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Background:Acute appendicitis (AA) is one of the most common causes of emergent surgeries. Many methods are used for its diagnosis.Objectives:This study was conducted to investigate the diagnostic value of MPV and RDW in acute appendicitis.Patients and Methods:This study was a retrospective multi-center cross sectional planned study. The study included 260 patients operated for AA and 158 patients as the control group. Groups were compared in terms of MPV, RDW, white blood cell count (WBC), neutrophil predominance (NP) and platelet count (PC).Results:MPV was significantly lower in AA group, compared to the control group (P < 0.001). The best cut-off level for MVP in AA was ≤ 7.3 fL and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy ratio were 45%, 89.2%, 87.3%, 49.6% and 61.7%, respectively. There was no significant difference between the two groups in terms of RDW and platelet values.Conclusions:MPV is a routinely measured parameter in complete blood count (CBC) and requires no additional cost. It significantly decreased in AA, having a greater sensitivity and NPV when combined with WBC and NP.

Background and purpose: Licofelone is a dual inhibitor of the cyclooxygenase and 5-lipoxygenase (5-LO) pathway, and has been developed for the treatment of inflammatory diseases. Here, we investigated the molecular mechanisms underlying the inhibition by licofelone of the formation of 5-LO products. Experimental approach: The efficacy of licofelone to inhibit the formation of 5-LO products was analysed in human isolated polymorphonuclear leukocytes (PMNL) or transfected HeLa cells, as well as in cell-free assays using respective cell homogenates or purified recombinant 5-LO. Moreover, the effects of licofelone on the subcellular redistribution of 5-LO were studied. Key results: Licofelone potently blocked synthesis of 5-LO products in Ca 2 þ -ionophore-activated PMNL (IC 50 ¼ 1.7 mM) but was a weak inhibitor of 5-LO activity in cell-free assays (IC 50 c10 mM). The structures of licofelone and MK-886, an inhibitor of the 5-LO-activating protein (FLAP), were superimposable. The potencies of both licofelone and MK-886 in ionophore-activated PMNL were impaired upon increasing the concentration of arachidonic acid, or under conditions where 5-LO product formation was evoked by genotoxic, oxidative or hyperosmotic stress. Furthermore, licofelone prevented nuclear redistribution of 5-LO in ionophore-activated PMNL, as had been observed for FLAP inhibitors. Finally, licofelone as well as MK-886 caused only moderate inhibition of the synthesis of 5-LO products in HeLa cells, unless FLAP was co-transfected. Conclusions and implications: Our data suggest that the potent inhibition of the biosynthesis of 5-LO products by licofelone requires an intact cellular environment and appears to be due to interference with FLAP.

Rational drug design is based on explicit or implicit structure-activity relationship models. Typically, receptor-based or ligand-based strategies are pursued, depending on the information available about known ligands and the receptor structure. Pseudoreceptor models combine the advantages of these two strategies and represent a unifying concept for both receptor mapping and ligand matching. They can provide an entry point for structure-based modelling in drug discovery projects that lack a high-resolution structure of the target. Here, we review the field of pseudoreceptor modelling techniques along with recent hit and lead finding applications, and critically discuss prerequisites, advantages and limitations of the various approaches.

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