Two-dimensional TiCl2: a high-performance anode material for Na-ion batteries with high capacity and fast diffusion.

Na-ion batteries (NIBs) have attracted a great deal of attention for large-scale electric energy storage due to their inherent safety, natural abundant resources, and low cost. The exploration of suitable anode materials is the major challenge in advancing NIB technology. On the basis of first-principles calculations, we systematically explore the potential performance of two-dimensional (2D) TiCl2 as an electrode material for NIBs. Monolayer TiCl2 can be easily exfoliated from the bulk structure with a small exfoliation energy of 0.64 J m-2. It shows good stability, as demonstrated by its high cohesive energy, positive phonon modes, and high thermal stability. Monolayer TiCl2 has high storage capacity (451.3 mA h g-1), low diffusion energy barrier (0.02-0.14 eV), moderate average open-circuit voltage (0.81 V), and small lattice change (2.37%). Moreover, bilayer TiCl2 can significantly enhance the Na adsorption strength but reduce the Na-ion diffusion ability. These results suggest that TiCl2 is a promising anode candidate for NIBs.

Understanding Data Noise and Uncertainty through Analysis of Replicate Samples in DNA-Encoded Library Selection.

By analyzing data sets of replicate DNA-Encoded Library (DEL) selections, an approach for estimating the noise level of the experiment has been developed. Using a logarithm transformation of the number of counts associated with each compound and a subset of compounds with the highest number of counts, it is possible to assess the quality of the data through normalizing the replicates and use this same data to estimate the noise in the experiment. The noise level is seen to be dependent on sequencing depth as well as specific selection conditions. The noise estimation is independent of any cutoff used to remove low frequency compounds from the data analysis. The removal of compounds with only 1-5 read counts greatly reduces some of the challenges encountered in DEL data analysis as it can reduce the data set by greater than 100-fold without impacting the interpretation of the results.

Employing Photocatalysis for the Design and Preparation of DNA-Encoded Libraries: A Case Study.

This Personal Account describes the authors' foray into DNA-encoded libraries. The article addresses several key aspects of this hit generation technology, from the development of new synthetic methodology to the subsequent conception, design, and delivery of a DNA-encoded library. In particular, we have been engaged in adapting photocatalytic reactions to the idiosyncratic requirements of DNA-encoded chemistry. We have chosen one such methodology, namely a photocatalytic [2+2] cycloaddition reaction, to showcase how we employed property-based computational analyses to guide the selection and validation of building blocks for the production of a library. Ultimately, these novel bond disconnections and design principles led to the assembly of a DNA-encoded library that is composed of structurally diverse compounds within largely desirable property space and, therefore, well positioned to deliver novel chemical matter for drug discovery programs.

Delineating the role of cooperativity in the design of potent PROTACs for BTK.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.

Designing DNA Encoded Libraries of Diverse Products in a Focused Property Space.

DNA encoded libraries (DEL) are being used as a complement or alternative to traditional high throughput screening (HTS). To maximize the chances of finding chemically attractive lead material that is appropriate for medicinal chemistry optimization, for example, in the Rule of Five compliant chemistry space, it is important to design DEL library compounds such that they are highly diverse and fall within a desired property space. Currently available library design methods can be classified as either monomer-based or product-based. As monomers may undergo significant structural changes when participating in a reaction, monomer based design can provide a poor representation of the properties of resultant DEL products. However, product-based design introduces a technical obstacle due to the enormous chemical design space for many DELs. Here a new method for monomer based selections is described using representative sublibraries as surrogates for fully enumerated DEL property-based optimization. Through a series of rational and systematic library enumerations and property calculations, building-block representatives are identified and representative sublibraries are defined to drive the optimization process. A published data set for a triazine library was used to demonstrate the effectiveness of the multiple objective optimization for six properties. All of the evaluated properties for the designed library are shown to consistently shift toward the desired property distribution as driven by the design criteria.

Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files.

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.

Deep understanding of structure-solubility relationship for a diverse set of organic compounds using matched molecular pairs.

Aqueous solubility is an important biopharmaceutical property in drug discovery and development. Although it has been studied for decades, the impact on solubility by the substructures (or fragments) of compounds are still not fully understood and characterized. This study aims to obtain fragment-solubility relationships using matched molecular pairs, and to provide further insight and suggestions for chemists on structural modifications to improve solubility profiles of drug-like molecules. A set of 2794 compounds with measured intrinsic aqueous solubility (logS) was fragmented into rings, linkers, and R groups using a controlled hierarchical fragmentation method. Then matched molecular pairs that differ by only one chemical transformation (i.e., addition or substitution of fragments) were identified and analyzed. The difference in solubility for each matched molecular pair was calculated, and the impact of the corresponding chemical transformation on solubility was investigated. The final product of this study was a fragment-solubility knowledgebase containing relative contributions to solubility of various medicinal chemistry design elements (R-groups, linkers, and rings). Structural modifications that might improve solubility profiles, that is, addition/deletion/substitution of fragments, could be derived from this knowledgebase. This knowledgebase could be used as an expert tool in lead optimization to improve solubility profiles of compounds, and the analysis method could be applied to study other biological and ADMET properties of organic compounds.

Selecting Approaches for Hit Identification and Increasing Options by Building the Efficient Discovery of Actionable Chemical Matter from DNA-Encoded Libraries.

Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.