High quality, small molecule-activity datasets for kinase research.

Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR) data.

Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway.

Unlabelled: Methane produced by the methanoarchaeon Methanobrevibacter smithii ( M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway.

Kinome-wide activity modeling from diverse public high-quality data sets.

Large corpora of kinase small molecule inhibitor data are accessible to public sector research from thousands of journal article and patent publications. These data have been generated employing a wide variety of assay methodologies and experimental procedures by numerous laboratories. Here we ask the question how applicable these heterogeneous data sets are to predict kinase activities and which characteristics of the data sets contribute to their utility.

Novel kinase inhibitors by reshuffling ligand functionalities across the human kinome.

Protein kinases remain among the most versatile and prospective therapeutic drug targets with currently 15 distinct compounds approved for use in humans and numerous clinical development programs. The vast majority of kinase inhibitors bind at the ATP site. Here we present an integrated workflow to amplify the rapidly increasing space of structurally resolved small molecule kinase ligands to generate novel inhibitors.

Prospective exploration of synthetically feasible, medicinally relevant chemical space.

We describe a novel approach to direct the exploration of chemical space in an effort to balance synthetic accessibility and medicinal relevancy prior to experimental work. Reaction transforms containing empirical reactivity and compatibility information are dynamically assembled into reaction sequences (vProtocols) utilizing commercially available starting material feedstock. These vProtocols are evolved and optimized by a genetic algorithm, which leverages fitness functions based on predicted properties of generated molecular products.

A simple and readily integratable approach to toxicity prediction.

A simple, highly extensible computational strategy to assess compound toxicity has been developed with the premise that a compound's toxicity can be gauged from the toxicities of structurally similar compounds. Using a reference set of 13645 compounds with reported acute toxicity endpoint dose data (oral, rat-LD(50) data normalized in mg/kg), a generic utility which assigns a compound the average toxicity of structurally similar compounds is shown to correlate well with reported values. In a leave-one-out simulation using the requirement that at least one structurally similar member in a "voting consortium" is present within a reference set, the strategy demonstrates a predictive correlation (q wedge 2) of 0.