PepSeA: Peptide Sequence Alignment and Visualization Tools to Enable Lead Optimization.

Therapeutic peptides offer potential advantages over small molecules in terms of selectivity, affinity, and their ability to target "undruggable" proteins that are associated with a wide range of pathologies. Despite their importance, current molecular design capabilities that inform medicinal chemistry decisions on peptide programs are limited. More specifically, there are unmet needs for structure-activity relationship (SAR) analysis and visualization of linear, cyclic, and cross-linked peptides containing non-natural motifs, which are widely used in drug discovery.

Diversity & tractability revisited in collaborative small molecule phenotypic screening library design.

Identification of purposeful chemical matter on a broad range of drug targets is of high importance to the pharmaceutical industry. However, disease-relevant but more complex hit-finding plans require flexibility regarding the subset of the compounds that we screen. Herein we describe a strategy to design high-quality small molecule screening subsets of two different sizes to cope with a rapidly changing early discovery portfolio.

Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki-Miyaura Cross Coupling Reaction.

Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki-Miyaura (S-M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S-M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed.

Plate-Based Phenotypic Screening for Pain Using Human iPSC-Derived Sensory Neurons.

Screening against a disease-relevant phenotype to identify compounds that change the outcome of biological pathways, rather than just the activity of specific targets, offers an alternative approach to find modulators of disease characteristics. However, in pain research, use of in vitro phenotypic screens has been impeded by the challenge of sourcing relevant neuronal cell types in sufficient quantity and developing functional end-point measurements with a direct disease link. To overcome these hurdles, we have generated human induced pluripotent stem cell (hiPSC)-derived sensory neurons at a robust production scale using the concept of cryopreserved "near-assay-ready" cells to decouple complex cell production from assay development and screening.

The Identification of Pivotal Transcriptional Factors Mediating Cell Responses to Drugs With Drug-Induced Liver Injury Liabilities.

Drug-induced liver injury (DILI) is a leading cause of drug attrition during drug development and a common reason for drug withdrawal from the market. The poor predictability of conventional animal-based approaches necessitates the development of alternative testing approaches. A body of evidence associates DILI with the induction of stress-response genes in liver cells.

CHEMGENIE: integration of chemogenomics data for applications in chemical biology.

Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data does not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness its potential. Here, we describe ongoing efforts at Merck & Co.

Deorphanization strategies for dark chemical matter.

The term dark chemical matter (DCM) was recently introduced for those molecules in a screening collection that have never shown any substantial biological activity despite having been tested in hundreds of high-throughput assays. It was suggested that, if hits emerge from this compound pool in future screening campaigns, they should be prioritized due to their exquisite selectivity profile. In this article we define DCM at our company and describe on-going efforts to shed light on the bioactivity of these apparently silent compounds, with an emphasis on multi-parametric profiling methods.

Amine promiscuity and toxicology analysis.

Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives).

Public Domain HTS Fingerprints: Design and Evaluation of Compound Bioactivity Profiles from PubChem's Bioassay Repository.

Molecular profiling efforts aim at characterizing the biological actions of small molecules by screening them in hundreds of different biochemical and/or cell-based assays. Together, these assays yield a rich data landscape of target-based and phenotypic effects of the tested compounds. However, submitting an entire compound library to a molecular profiling panel can easily become cost-prohibitive.

Dark chemical matter as a promising starting point for drug lead discovery.

High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM).

ConTour: Data-Driven Exploration of Multi-Relational Datasets for Drug Discovery.

Large scale data analysis is nowadays a crucial part of drug discovery. Biologists and chemists need to quickly explore and evaluate potentially effective yet safe compounds based on many datasets that are in relationship with each other. However, there is a lack of tools that support them in these processes.

Experimental design strategy: weak reinforcement leads to increased hit rates and enhanced chemical diversity.

High Throughput Screening (HTS) is a common approach in life sciences to discover chemical matter that modulates a biological target or phenotype. However, low assay throughput, reagents cost, or a flowchart that can deal with only a limited number of hits may impair screening large numbers of compounds. In this case, a subset of compounds is assayed, and in silico models are utilized to aid in iterative screening design, usually to expand around the found hits and enrich subsequent rounds for relevant chemical matter.

Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies.

A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment "hits." However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques.

The opportunities of mining historical and collective data in drug discovery.

Vast amounts of bioactivity data have been generated for small molecules across public and corporate domains. Biological signatures, either derived from systematic profiling efforts or from existing historical assay data, have been successfully employed for small molecule mechanism-of-action elucidation, drug repositioning, hit expansion and screening subset design. This article reviews different types of biological descriptors and applications, and we demonstrate how biological data can outlive the original purpose or project for which it was generated.

Composition and applications of focus libraries to phenotypic assays.

The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections.

Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes.

We introduce a novel strategy to sample bioactive chemical space, which follows-up on hits from fragment campaigns without the need for a crystal structure. Our results strongly suggest that screening a few hundred or thousand fragments can substantially improve the selection of small-molecule screening subsets. By combining fragment-based screening with virtual fragment linking and HTS fingerprints, we have developed an effective strategy not only to expand from low-affinity hits to potent compounds but also to hop in chemical space to substantially novel chemotypes.

Entourage: visualizing relationships between biological pathways using contextual subsets.

Biological pathway maps are highly relevant tools for many tasks in molecular biology. They reduce the complexity of the overall biological network by partitioning it into smaller manageable parts. While this reduction of complexity is their biggest strength, it is, at the same time, their biggest weakness.

Bioturbo similarity searching: combining chemical and biological similarity to discover structurally diverse bioactive molecules.

Virtual screening using bioactivity profiles has become an integral part of currently applied hit finding methods in pharmaceutical industry. However, a significant drawback of this approach is that it is only applicable to compounds that have been biologically tested in the past and have sufficient activity annotations for meaningful profile comparisons. Although bioactivity data generated in pharmaceutical institutions are growing on an unprecedented scale, the number of biologically annotated compounds still covers only a minuscule fraction of chemical space.

Biodiversity of small molecules--a new perspective in screening set selection.

How is the 'diversity' of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound-target diversity.

Systematic assessment of compound series with SAR transfer potential.

Compound series with different core structures that contain pairs of analogs with corresponding substitution patterns and similar activity represent structure-activity relationship (SAR) transfer events. On the basis of the matched molecular pair (MMP) formalism and linear regression analysis of compound potencies, a general approach is introduced for the identification of SAR transfer series (SAR-TS) and SAR-TS with regular potency progression (SAR-TS-RP). We have systematically extracted such series from public domain compound data and analyzed their size distribution and structural characteristics.

SAR matrices: automated extraction of information-rich SAR tables from large compound data sets.

We introduce the SAR matrix data structure that is designed to elucidate SAR patterns produced by groups of structurally related active compounds, which are extracted from large data sets. SAR matrices are systematically generated and sorted on the basis of SAR information content. Matrix generation is computationally efficient and enables processing of large compound sets.

BindingDB and ChEMBL: online compound databases for drug discovery.

Public domain repositories of compound structures and activity data are indispensable tools for many aspects of pharmaceutical research, especially in academic environments. Such databases provide essential resources for structure-activity data mining and the evaluation of chemoinformatics and drug design methods. They are also important to support scientific interactions between commercial and academic environments.