Galaxy (homepage: https://galaxyproject.org, main public server: https://usegalaxy.org) is a web-based scientific analysis platform used by tens of thousands of scientists across the world to analyze large biomedical datasets such as those found in genomics, proteomics, metabolomics and imaging. Started in 2005, Galaxy continues to focus on three key challenges of data-driven biomedical science: making analyses accessible to all researchers, ensuring analyses are completely reproducible, and making it simple to communicate analyses so that they can be reused and extended. During the last two years, the Galaxy team and the open-source community around Galaxy have made substantial improvements to Galaxy's core framework, user interface, tools, and training materials. Framework and user interface improvements now enable Galaxy to be used for analyzing tens of thousands of datasets, and >5500 tools are now available from the Galaxy ToolShed. The Galaxy community has led an effort to create numerous high-quality tutorials focused on common types of genomic analyses. The Galaxy developer and user communities continue to grow and be integral to Galaxy's development. The number of Galaxy public servers, developers contributing to the Galaxy framework and its tools, and users of the main Galaxy server have all increased substantially.

/pdf/the-galaxy-platform-for-accessible-reproducible-and-onagm5kjs7.pdf

The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update

This review describes a multidimensional treatment of molecular recognition phenomena involving aromatic rings in chemical and biological systems. It summarizes new results reported since the appearance of an earlier review in 2003 in host-guest chemistry, biological affinity assays and biostructural analysis, data base mining in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB), and advanced computational studies. Topics addressed are arene-arene, perfluoroarene-arene, S⋅⋅⋅aromatic, cation-π, and anion-π interactions, as well as hydrogen bonding to π systems. The generated knowledge benefits, in particular, structure-based hit-to-lead development and lead optimization both in the pharmaceutical and in the crop protection industry. It equally facilitates the development of new advanced materials and supramolecular systems, and should inspire further utilization of interactions with aromatic rings to control the stereochemical outcome of synthetic transformations.

Aromatic rings in chemical and biological recognition: energetics and structures.

Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.

Targeting bromodomains: epigenetic readers of lysine acetylation

Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein-ligand binding, protein-protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields.

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

Cation-π interaction: its role and relevance in chemistry, biology, and material science.

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

Structural basis of PROTAC cooperative recognition for selective protein degradation.

Noncovalent interactions have a constitutive role in the science of intermolecular relationships, particularly those involving aromatic rings such as π–π and cation–π. In recent years, anion–π contact has also been recognized as a noncovalent bonding interaction with important implications in chemical processes. Yet, its involvement in biological processes has been scarcely reported. Herein we present a large-scale PDB analysis of the occurrence of anion–π interactions in proteins and nucleic acids. In addition we have gone a step further by considering the existence of cooperativity effects through the inclusion of a second noncovalent interaction, i.e. π-stacking, T-shaped, or cation–π interactions to form anion–π–π and anion–π–cation triads. The statistical analysis of the thousands of identified interactions reveals striking selectivities and subtle cooperativity effects among the anions, π-systems, and cations in a biological context. The reported results stress the importance of anion–π interactions and the cooperativity that arises from ternary contacts in key biological processes, such as protein folding and function and nucleic acids–protein and protein–protein recognition. We include examples of anion–π interactions and triads putatively involved in enzymatic catalysis, epigenetic gene regulation, antigen–antibody recognition, and protein dimerization.

/pdf/a-thorough-anion-p-interaction-study-in-biomolecules-on-the-23fi749m7q.pdf

A thorough anion–π interaction study in biomolecules: on the importance of cooperativity effects

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

/pdf/structure-based-design-of-a-macrocyclic-protac-10qk06ljz9.pdf

Structure-Based Design of a Macrocyclic PROTAC.

Bacteria from the genus Streptomyces are very important for the production of natural bioactive compounds such as antibiotic, antitumour or immunosuppressant drugs. Around two-thirds of all known natural antibiotics are produced by these bacteria. An enormous quantity of crucial data related to this genus has been generated and published, but so far no freely available and comprehensive database exists. Here, we present StreptomeDB (http://www.pharmaceutical-bioinformatics.de/streptomedb/). To the best of our knowledge, this is the largest database of natural products isolated from Streptomyces. It contains >2400 unique and diverse compounds from >1900 different Streptomyces strains and substrains. In addition to names and molecular structures of the compounds, information about source organisms, references, biological role, activities and synthesis routes (e.g. polyketide synthase derived and non-ribosomal peptides derived) is included. Data can be accessed through queries on compound names, chemical structures or organisms. Extraction from the literature was performed through automatic text mining of thousands of articles from PubMed, followed by manual curation. All annotated compound structures can be downloaded from the website and applied for in silico screenings for identifying new active molecules with undiscovered properties.

/pdf/streptomedb-a-resource-for-natural-compounds-isolated-from-2mlto47dm8.pdf

StreptomeDB: a resource for natural compounds isolated from Streptomyces species

Chromatin remodeling is a key epigenetic mechanism of gene expression regulation controlled through the posttranscriptional modification of histones. Several enzymes, including histone deacetylases and lysine methyltransferases, add or remove functional groups at a variety of residues on histone tails. The recognition of this histone code by “reader” proteins, such as bromodomains (BRDs) and tudor domains, has a critical impact in the regulation of gene expression. The human genome encodes up to 61 different BRDs present in transcriptional co-regulators and chromatin modifying enzymes, including histone acetyl transferases and the bromodomain extra-terminal domain (BET) family. They specifically recognize e-N-acetylated lysine residues (Kac). BRDs fold into an evolutionary conserved four anti-parallel helix motif, linked by diverse loop regions of variable length (ZA and BC loops), which define the Kac binding site. [2] In most BRDs, this site features an asparagine residue mainly responsible for substrate recognition. The biological function of BRDs and their potential as therapeutic targets have been thoroughly reviewed. The large amount of crystallographic data available for most BRDs has recently shown the druggability of human BRDs, including the BET subfamily, namely BRD2, BRD3, BRD4, and BRDT, which modulate gene expression by recruiting transcriptional regulators to specific genomic locations. BRD2 and BRD4 have crucial roles in cell cycle control of mammalian cells. Along with BRD3, they are functionally linked to pathways important for cellular viability and cancer signaling and are co-regulators in obesity and inflammation. Specifically, BRD4 has been characterized as a key determinant in acute myeloid leukemia, multiple myeloma, Burkitt s lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. Because of its continued association with Kac in mitotic chromosomes, BRD4 has been postulated to be important for the maintenance of epigenetic memory. Small molecules that inhibit BRD4 have potential as antiinflammatory, antiviral, and anticancer agents. Anticancer activity is mainly due to down-regulation of the key oncogene c-MYC. Recently, cytotoxicity in LAC cells by BRD4 inhibition has been related to suppression of the oncogenic transcription factor FOSL1 and its targets. Currently, two 1,4-diazepine derivatives, namely (+)-JQ1 and I-BET, are in preclinical development in cancer and inflammation, respectively, as potent antagonists of the BET bromodomains BRD2, BRD3, and BRD4. Recent fragment-based screenings and QSAR-based lead optimizations for the discovery of small molecules with BRD4 inhibitory activity have shed a few new relevant chemical scaffolds, including Compound 6a, an isoxazole derivative at an initial developmental stage in the clinics. During recent years, a large amount of structural knowledge about the binding features of inhibitors of BRD4 has become available by means of X-ray crystallography, providing an invaluable resource for drug discovery. The three key areas of interaction in ligand-BET bromodomain complexes are the acetyl-lysine recognition site, the WPF shelf, and the ZA channel (Figure 1c). On this basis, we performed a highthroughput virtual screening experiment using a library containing more than 7 million small molecules, aiming at the identification of novel inhibitors of the first bromodomain of BRD4 (BRD4(1); Supporting information).We selected 22

Xavier Lucas

Papers

Structural basis of PROTAC cooperative recognition for selective protein degradation.

A thorough anion–π interaction study in biomolecules: on the importance of cooperativity effects

Structure-Based Design of a Macrocyclic PROTAC.

StreptomeDB: a resource for natural compounds isolated from Streptomyces species

4‐Acyl Pyrroles: Mimicking Acetylated Lysines in Histone Code Reading