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 3 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.

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.

Heteroaromatic rings of the future.

Small aromatic ring systems are of central importance in the development of novel synthetic protein ligands. Here we generate a complete list of 24,847 such ring systems. We call this list and associated annotations VEHICLe, which stands for virtual exploratory heterocyclic library. Searches of literature and compound databases, using this list as substructure queries, identified only 1701 as synthesized. Using a carefully validated machine learning approach, we were able to estimate that the number of unpublished, but synthetically tractable, VEHICLe rings could be over 3000. However, analysis also shows that the rate of publication of novel examples to be as low as 5-10 per year. With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered.

Imidazopyridines as VLA-4 integrin antagonists.

We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure-activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule.

Synthesis and SAR of aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors.

The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.

Improved synthesis of (+/-)-4,12-dihydroxy[2.2]paracyclophane and its enantiomeric resolution by enzymatic methods: planar chiral (R)- and (S)-phanol.

(+/-)-4,12-Dihydroxy[2.2]paracyclophane [(+/-)-PHANOL] is readily prepared from [2.2]paracyclophane by an improved synthetic protocol. Enzymatic kinetic resolution of its bis-acetate proceeds with good enantioselection. Separation, hydrolysis, and recrystallization provides both enantiomers of PHANOL in high enantiopurity.