CACHE (Critical Assessment of Computational Hit-finding Experiments): A public–private partnership benchmarking initiative to enable the development of computational methods for hit-finding

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small-molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small-molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared and openly published. CACHE will launch three new benchmarking exercises every year. The outcomes will be better prediction methods, new small-molecule binders for target proteins of importance for fundamental biology or drug discovery and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins. [Figure not available: see fulltext.

Quantifying Water-Mediated Protein–Ligand Interactions in a Glutamate Receptor: A DFT Study

It is becoming increasingly clear that careful treatment of water molecules in ligand–protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand–system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design

Human commensalism in the house sparrow

SAETRE G-P, Riyahi S, ALIABADIAN M, et al. Single origin of human commensalism in the house sparrow. Journal of Evolutionary Biology. 2012;25(4):788-796

Regulatory roles and functions in information-based regulation: a systematic review

Information-based regulation occurs when regulators use information to drive changes in behaviours in order to achieve public policy objectives. Information-based regulation has emerged as an alternative way to regulate firms compared with more traditional direct command-and-control and market-based policy instruments within the contemporary regulatory state. Despite growing international interest, challenges remain in understanding the roles for regulators in information-based regulation, the functions of regulators in shaping and leveraging information flows, and the administrative capacities required to fulfil them. Based on a systematic review methodology, this article synthesises the findings of 130 peer-reviewed articles in the environmental, energy and food policy areas. It develops a typology of functions for regulators and outlines the new administrative capacities required in the contemporary regulatory state, particularly in standard setting, assurance and intermediation, and smart data management. Points for practitioners: Regulation by information is becoming popular in many part of the world beyond its original genesis in the US and other developed countries. The design and implementation of such schemes creates new challenges for regulators. Our review integrates relevant research in three policy areas (environment, food and energy) and develops a new typology of functions performed by regulators. The article is the first to discuss how the roles and functions of regulators need to change in the contemporary information and regulatory environment. It also emphasises the importance of regulatory involvement in information-based regulation, which has traditionally been seen as a deregulatory approach