Establishing a reliable framework for harnessing the creative power of the scientific crowd.

Discovering new medicines is difficult and increasingly expensive. The pharmaceutical industry has responded to this challenge by embracing open innovation to access external ideas. Historically, partnerships were usually bilateral, and the drug discovery process was shrouded in secrecy. This model is rapidly changing. With the advent of the Internet, drug discovery has become more decentralised, bottom-up, and scalable than ever before. The term open innovation is now accepted as just one of many terms that capture different but overlapping levels of openness in the drug discovery process. Many pharmaceutical companies recognise the advantages of revealing some proprietary information in the form of results, chemical tools, or unsolved problems in return for valuable insights and ideas. For example, such selective revealing can take the form of openly shared chemical tools to explore new biological mechanisms or by publicly admitting what is not known in the form of an open call. The essential ingredient for addressing these problems is access to the wider scientific crowd. The business of crowdsourcing, a form of outsourcing in which individuals or organisations solicit contributions from Internet users to obtain ideas or desired services, has grown significantly to fill this need and takes many forms today. Here, we posit that open-innovation approaches are more successful when they establish a reliable framework for converting creative ideas of the scientific crowd into practice with actionable plans.

Target 2035 - update on the quest for a probe for every protein.

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

Dataset of the frequency patterns of publications annotated to human protein-coding genes, their protein products and genetic relevance.

We present data concerning the distribution of scientific publications for human protein-coding genes together with their protein products and genetic relevance. We annotated the gene2pubmed dataset Maglott et al., 2007 provided by the NCBI (National Center for Biotechnology Information) with publication years, genetic metadata corresponding to Online Mendelian Inheritance in Man (OMIM) Hamosh et al., 2005 entries and the frequency of their appearance in Genome-Wide Association Studies (GWAS) Buniello et al., 2019 provided by the European Bioinformatics Institute (EBI) using the KNIME® Analytics Platform Berthold et al., 2008. The results of this data integration process comprise two datasets: 1) A dataset containing information on all human protein-coding genes that can be used to analyse the number of scientific publications in context of the potential disease relevance of the individual genes. 2) A table with the annual and cumulated number of PubMed entries. For further interpretation of the data presented in this article, please see the research article 'Target 2035 - probing the human proteome' by Carter et al. https://doi.org/10.1016/j.drudis.2019.06.020 Carter et al., 2019.

Target 2035: probing the human proteome.

Biomedical scientists tend to focus on only a small fraction of the proteins encoded by the human genome despite overwhelming genetic evidence that many understudied proteins are important for human disease. One of the best ways to interrogate the function of a protein and to determine its relevance as a drug target is by using a pharmacological modulator, such as a chemical probe or an antibody. If these tools were available for most human proteins, it should be possible to translate the tremendous advances in genomics into a greater understanding of human health and disease, and catalyze the creation of innovative new medicines. Target 2035 is a global federation for developing and applying new technologies with the goal of creating chemogenomic libraries, chemical probes, and/or functional antibodies for the entire proteome.

Donated chemical probes for open science.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke.

We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice. We found that the hydroxyl function in the 4'-position is crucial for improving the sodium channel blocking properties. Moreover, the stereochemistry and the topology of the N-linked side chain also influence this interaction. Indeed, the affinity is improved by an aromatic substitution in the side chain. By modifying the N substituent and the substitution pattern of the hydroxyl function, we were able to discover (2R)-[2alpha,3(S),6alpha]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride. This compound was chosen as the best candidate for further pharmacological investigations.