Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.

Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.Work in DRS’s laboratory is supported by the the European Union, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Wellcome Trust. Work in ARV’s laboratory is supported by the Medical Research Council and Wellcome Trust. Work in DJH's laboratory is supported by the Medical Research Council under grant ML/L007266/1. All calculations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and were funded by the EPSRC under grants EP/F032773/1 and EP/J017639/1. GJM and ARV are affiliated with PhoreMost Ltd, Cambridge. We thank Alicia Higueruelo and John Skidmore for helpful discussions.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.chembiol.2015.04.01

Two information aggregation mechanisms for predicting the opening weekend box office revenues of films: Box-office Prophecy and Guess of Guesses

Field tests were conducted on two newinformation aggregationmechanism designs. The mechanisms were designed to collect information held as intuitions about opening weekend box office revenues for movies in Australia. The principles on which the mechanisms operate and their capacity to collect information are explored. A pari-mutuel mechanism produces a predicted probability distribution over box office amounts that is, with the exception of very small films, indistinguishable from the actual revenues. The second mechanism is based on guessing the guesses of others and when applied under conditions where incentives for accuracy are unavailable still performs well against data

Two Information Aggregation Mechanisms for Predicting the Opening Weekend Box Office Revenues of Films: Boxoffice Prophecy and Guess of Guesses

Successful field tests were conducted on two new Information Aggregation Mechanisms (IAMs). The mechanisms collected information held as intuitions about opening weekend box office revenues for movies in Australia. Participants were film school students. One mechanism is similar to parimutuel betting that produces a probability distribution over box office amounts. Except for “art house films”, the predicted distribution is indistinguishable from the actual revenues. The second mechanism is based on guesses of the guesses of others and applied when incentives for accuracy could not be used. It tested well against data and contains information not encompassed by the first mechanism

Shaped nozzles for cryogenic buffer gas beam sources

Cryogenic buffer gas beams are important sources of cold molecules. In this work we explore the use of a converging-diverging nozzle with a buffer-gas beam. We find that, under appropriate circumstances, the use of a nozzle can produce a beam with improved collimation, lower transverse temperatures, and higher fluxes per solid angle

Kinetic Resolution in Asymmetric Epoxidation using Iminium Salt Catalysis

The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are described, providing up to 99% ee in the epoxidation of racemic cis-chromenes