Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• selection of hypervalent iodine compounds have also been assessed in silico to determine the strengths of their σ-holes (Figure 3). Togni’s CF3-benziodoxole reagent (I-5, 0.029 e) possessed the weakest σ-hole from among those analyzed, consistent with monovalent iodobenzene (I-2) [72]. Difluoroiodobenzene

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• sequencing technology has resulted in the introduction of an alternative approach towards novel natural product scaffolds: Genome mining. Genome mining is an in-silico natural product discovery strategy in which sequenced genomes are analyzed for the potential of the associated organism to produce natural

• already known metabolites [14]. In-silico dereplication can be performed on two levels: First, BGCs identified by genome mining can be compared to characterized BGCs [17]. Second, in many cases NP core structures can be predicted from genome sequence information and the predicted structures can then be

• associated NP [56][57][58]. In silico dereplication to eliminate BGCs associated with known NPs is one of the major functions of genome mining to avoid the time-consuming and costly re-isolation of known NPs. For instance, the antiSMASH platform compares putative BGCs with reference databases to detect BGCs

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• metabolic functions. Here, we describe a new UbiA-like prenyltransferase (Ptase) Ubi-297 encoded in a conserved operon of several bacterial taxa, including marine Flavobacteria and the genus Sacchromonospora. In silico analysis of Ubi-297 homologs indicated that members of this Ptase group are composed of

• their substrate scope by heterologous production and enzymatic bioassays. Results of our study showcase that marine bacteria harbor still a broad unexplored enzymatic repertoire. Results and Discussion In silico analysis of Ptases in marine Flavobacteria and the genus Saccharomonospora In a first step

• obtained after washing and ultracentrifugation. Substrate specificity of UbiA-297 Based on our in silico analysis and previous mass-spectrometry-guided metabolomic analysis of marine Flavobacteria and members of the genus Saccharomonospora [29][30], we anticipated hydroxylated aromatic or even quinoline

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• underexplored. However, in silico genome mining identified multiple secondary metabolite biosynthetic gene clusters in selected strains from minor actinomycetes genera, implying their comparable biosynthetic capacities to those of the already proven genera [19]. Encouraged by these reports, we examined the

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• interactions between anionic sulphate groups and the primary amine group present in doxorubicin which confers a positive charge under physiological conditions. This interaction was confirmed by in silico modelling. While the carriers did not show any cytotoxicity, cell viability was reduced in the presence of

A systems-based framework to computationally describe putative transcription factors and signaling pathways regulating glycan biosynthesis

• Theodore Groth,
• Rudiyanto Gunawan and
• Sriram Neelamegham

Beilstein J. Org. Chem. 2021, 17, 1712–1724, doi:10.3762/bjoc.17.119

• experimentally discovering the TFs regulating glycosylation. The findings would likely vary between cell types, and thus additional efforts are necessary before a wet-lab-validated framework emerges. Orthogonal datasets containing other ChIP-Seq and omics data may also enhance in silico validation. Some examples

• , degree of experimental evidence, and the statistical approaches taken by other investigators can influence the set of TF–gene relationships found. In addition to in silico validation, perturbational experiments, such as performing CRISRP-Cas9 knockouts with single-cell RNA-Seq, followed by glycomics

Simulating the enzymes of ganglioside biosynthesis with Glycologue

• Andrew G. McDonald and
• Gavin P. Davey

Beilstein J. Org. Chem. 2021, 17, 739–748, doi:10.3762/bjoc.17.64

• those of the central nervous system, where they function in intercellular recognition and communication. We describe an in silico method for determining the metabolic pathways leading to the most common gangliosides, based on the known enzymes of their biosynthesis. A network of 41 glycolipids is

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• high anticonvulsant activity after tests in silico and in vivо [7]. Moreover, compounds C and D reveal high activity as casein kinase 2 (CK2) inhibitor and high antitumor activity which makes compounds to be promising anticancer drugs [8]. There are quite a few methods for the synthesis of the

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• of CPD with the model nitrostyrene 1h was simulated in silico to predict the reaction pathway, the reaction rate constants, and the activation enthalpies. Density functional theory calculations were conducted for the reactants, products, and transition states using the B3LYP [64][65][66] and M062X

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• characterisation of the binding reaction. Computational methods are used to predict PPIs and interfaces. The advantage of performing in silico experiments includes narrowing down the number of the binding partners to be tested in vitro or in vivo. Computational methods include supervised machine learning, where

Synthesis of purines and adenines containing the hexafluoroisopropyl group

• Viacheslav Petrov,
• Rebecca J. Dooley,
• Alexander A. Marchione,
• Elizabeth L. Diaz,
• Brittany S. Clem and
• William Marshall

Beilstein J. Org. Chem. 2020, 16, 2739–2748, doi:10.3762/bjoc.16.224

• rotamers in hand, an Eyring plot was generated, and the enthalpy and entropy of activation were derived (Table 2). The structural identification of the major and minor rotamers was not attempted by NMR, but in silico investigations of 3a supported the intuitive notion that the rotamer of lower energy was

Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen–antibody binding

• Christopher B. Barnett,
• Tharindu Senapathi and
• Kevin J. Naidoo

Beilstein J. Org. Chem. 2020, 16, 2540–2550, doi:10.3762/bjoc.16.206

• approach by investigating the in-silico binding of a peptide and glycopeptide epitope of the glycoprotein Mucin 1 (MUC1) binding with the antibody AR20.5. To study the binding, we performed molecular dynamics simulations using OpenMM and then used the Galaxy platform for data analysis. The same analysis

• under observation, could be readily applied to other binding problems as part of a general strategy in drug design or mechanistic analysis. Keywords: binding; conformation; Galaxy; glycoprotein; in silico; Introduction A typical sequence of events in research and discovery is noticing a critical

• . and others [14][16] provides a foundation for further investigation into the binding of glycopeptide antigens to antibodies using computational modeling. Molecular dynamics (MD) simulations and analysis thereof are a well-known ingredient of the in-silico process for mechanistic screening of

Computational tools for drawing, building and displaying carbohydrates: a visual guide

• Kanhaya Lal,
• Rafael Bermeo and
• Serge Perez

Beilstein J. Org. Chem. 2020, 16, 2448–2468, doi:10.3762/bjoc.16.199

• hand, the Glycan Modeler allows in silico N-/O-glycosylation for glycan-protein complexes and generates a “most relevant” glycan structure through Glycan Fragment Database (GFDB) [68] search which gives proper orientations relative to the target protein. In the absence of target glycan sequence in GFDB

Design, synthesis and application of carbazole macrocycles in anion sensors

• Alo Rüütel,
• Ville Yrjänä,
• Sandip A. Kadam,
• Indrek Saar,
• Mihkel Ilisson,
• Astrid Darnell,
• Kristjan Haav,
• Tõiv Haljasorg,
• Lauri Toom,
• Johan Bobacka and
• Ivo Leito

Beilstein J. Org. Chem. 2020, 16, 1901–1914, doi:10.3762/bjoc.16.157

• . Conclusion To construct a functional chemical sensor, extensive interdisciplinary effort is required. A variety of problems must be addressed in several development stages, all of which were attended to in this work. The conceptual design of macrocyclic anion receptors led to in silico complexation studies

• , Laboratory of Molecular Science and Engineering, Åbo Akademi University, Biskopsgatan 8, FI-20500 Turku/Åbo, Finland 10.3762/bjoc.16.157 Abstract Carboxylate sensing solid-contact ion-selective electrodes (ISEs) were created to provide a proof-of-concept ISE development process covering all aspects from in

• silico ionophore design to functional sensor characterization. The biscarbazolylurea moiety was used to synthesize methylene-bridged macrocycles of different ring size aiming to fine tune selectivity towards different carboxylates. Cyclization was achieved with two separate strategies, using either amide

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• the potential of the in silico methods for the design of new GlfT2 inhibitors. Target ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones 1‒3. Molecular representation of the best binding poses of the four compounds with the predicted highest affinity. (A) 1bα, (B) 2c, (C) 3c and (D) 1cβ. The molecule

• mechanism studies using computational chemistry methods. The probable reaction mechanisms were studied by hybrid DFT QM/MM molecular dynamics simulations [11] where the possible transition state (TS) structures were localized. The observation of the possible TS structure opens the opportunities for the in

• silico based design of possible GlfT2 inhibitors that mimic the TS structure. The galactofuranosyltransferase GlfT2 is a bisubstrate enzyme with a single catalytic domain and its catalytic reaction transition state shares some structural similarities with the previously modeled N

In silico rationalisation of selectivity and reactivity in Pd-catalysed C–H activation reactions

• Liwei Cao,
• Mikhail Kabeshov,
• Steven V. Ley and
• Alexei A. Lapkin

Beilstein J. Org. Chem. 2020, 16, 1465–1475, doi:10.3762/bjoc.16.122

• for in silico prediction of reaction outcomes. This approach was tested on the for green chemistry important class of C–H activation reactions. Whilst this study does not completely solve the problem of developing a robust chemical reaction, it offers an approach that is complementary to efforts of

• big challenge remaining which is to apply the computational analysis to a large number of mechanistically different transformations, both described and novel, in order to start generating accurate in silico reaction predictions. Here, we report an algorithm with high-performance computing (HPC

• products, as well as the relative reactivity of the substrates [27]. For the PA mechanism, it has not been shown that the Hammond postulate can also be employed. Nevertheless, it is still reasonable to propose that the Hammond postulate can similarly be applied as a first approximation to produce in silico

A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus Pseudosporangium

• Shun Saito,
• Kota Atsumi,
• Tao Zhou,
• Keisuke Fukaya,
• Daisuke Urabe,
• Naoya Oku,
• Md. Rokon Ul Karim,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1100–1110, doi:10.3762/bjoc.16.97

• ], medium supplements for selective microbial/cell culture [6][7][8], or biochemical reagents for pharmacological/chemical biology studies [9] and continue to be indispensable to support and improve human welfare and social life. In recent years, in accordance with the advancement of genome and in silico

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• -derived terpene-modifying enzymes. In addition, the fact that several CYPs have been shown to have relaxed substrate specificity, act on several intermediates, or catalyze multiple reactions, further complicates the in silico prediction. (Bio)synthetic production of complex terpenoids Heterologous

• /surrogate redox partners or fusing CYPs with redox partners [80][136][141][150][151]. One common observation is that CYP activity is not able to match the high flux of isoprenoids, leaving a significant portion of terpenes unmodified. Solutions to this problem, such as in silico redox partner prediction

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• physiological conditions. The broad success [22] of this strategy since 2004 [19] suggests that even though careful in silico modeling is a standard step in photoprobe development [22], this is always performed with unhydrolyzed conjugates. Perhaps for long-term use in vivo an additional modeling step involving

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• aromatic function [30][36][37][38] (Table 2 and Scheme 1), which significantly affect the product profile. Further support for the reaction mechanism was generated by gas-phase calculations [33][34] as well as in silico multiscale modeling [37], which suggest an active role of the enzyme during catalysis

Towards the preparation of synthetic outer membrane vesicle models with micromolar affinity to wheat germ agglutinin using a dialkyl thioglycoside

• Dimitri Fayolle,
• Nathalie Berthet,
• Bastien Doumeche,
• Olivier Renaudet,
• Peter Strazewski and
• Michele Fiore

Beilstein J. Org. Chem. 2019, 15, 937–946, doi:10.3762/bjoc.15.90

• adjuvants, glycolipid–phospholipid drug delivery systems and for the formulation of GVs that can be used as tools to bind to various bacterial lectins depending on the mono- or disaccharides used. As a first and relevant conclusion, in silico and in vitro studies demonstrated that two of those compounds

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• species [12]. The presence of mycobacterial lectins was further supported by Abhinav et al. using in silico genome analysis. A bioinformatics homology-based search of lectin-encoding gene regions in 30 fully or partially sequenced mycobacterial genomes identified 94 potential glycan-binding proteins. The

• ]. Interestingly, anti-HBHA antibodies have been detected in the sera of TB patients [82]. Thus, a humoral immune response to HBHA might also be connected to a reduced dissemination of Mtb from human lungs. Apart from the potential lectins predicted by in silico genome analysis, a C-type lectin-like carbohydrate

• . Interestingly, one of the T4P-associated genes is Rv3659, previously identified by in silico genome analysis as coding for a potential mycobacterial lectin (see above) [78]. Although the related protein is most likely involved in pili assembly, it is not inconceivable that T4P have carbohydrate-binding

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• validate these in silico screened hits, their ability to inhibit the Bacillus subtilis NusB/NusE PPI was examined. Gratifyingly, compounds 40 and 41 (Figure 9) exhibited an inhibition of the NusB/NusE interaction at 25 μM higher than 50% and IC50 values in the low micromolar range (6.1 and 19.8 μM

• , was reported very recently by Ma et al. [96]. After an in silico screening of a combination of the previously mentioned mini-Maybridge library and the Enamine antibacterial library, seven hits were identified. Among all of them, the nitrophenol derivative MC4 (43, Figure 9) was able to inhibit NusB

• a challenge. Thus far, extensive in silico and high throughput screening campaigns of libraries of compounds, combinatorial synthesis and structure-based design approaches, biophysical screening techniques (i.e., fluorescence polarization, surface plasmon resonance and differential scanning

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• none of these compounds an X-ray structure in complex with PqsD has been reported although the apoenzyme as well as a substrate-bound form has been successfully crystallized [49]. Using these coordinates, employing in silico methods allowed proposing plausible binding poses for prototypic analogues of

• before [59]. Further interesting starting points for the discovery of PqsD inhibitors have been provided by a dedicated screening campaign involving fragment-based hit discovery, in silico screening and a similarity-guided approach starting from FabH inhibitors [60]. The most potent hit 16 of this study

Steric “attraction”: not by dispersion alone

• Ganna Gryn’ova and
• Clémence Corminboeuf

Beilstein J. Org. Chem. 2018, 14, 1482–1490, doi:10.3762/bjoc.14.125

• Architectures, Crafted in silico” and from the European Research Council (ERC Grant 306528 COMPOREL). The authors also thank Prof. Konrad Patkowski (Auburn University) and Mr. Kun-Han Lin (EPFL) for helpful comments.