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.

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• the release of the active drug will not be perturbed. In case that the drug binds through recognition of a specific receptor, in silico approaches have to be recruited in order to rationally select the location of the drug that will be chemically modified [18]. Furthermore, it must be sufficiently

Is the tungsten(IV) complex (NEt₄)₂[WO(mnt)₂] a functional analogue of acetylene hydratase?

• Matthias Schreyer and
• Lukas Hintermann

Beilstein J. Org. Chem. 2017, 13, 2332–2339, doi:10.3762/bjoc.13.230

• (ethanal; 3) by redox-neutral addition of water (Scheme 1a) [2][3][4][5][6]. Even based on X-ray structural data of the enzyme [4], the catalytic reaction mechanism was not immediately obvious [4][7]. Several mechanisms have so far been considered and investigated in silico [8][9][10][11][12]. The most

• to aldehydes (Scheme 2b) [21][22][23]. Thus, we wondered if tungsten complex 1, and by analogy acetylene hydratase, is an alkyne hydration catalysts that follows a vinylidene–metal mechanism. This idea has also been considered by others [7][8][9][10] and was investigated in silico by Hillier and co

Biomimetic molecular design tools that learn, evolve, and adapt

• David A Winkler

Beilstein J. Org. Chem. 2017, 13, 1288–1302, doi:10.3762/bjoc.13.125

• , medicine and engineering. Automation, robotics, artificial intelligence, and evolutionary algorithms are now converging to generate what might broadly be called in silico-based adaptive evolution of materials. These methods are being applied to organic chemistry to systematize reactions, create synthesis

• methods and their potential impacts in chemistry, engineering, and medicine. Keywords: automated chemical synthesis; deep learning; evolutionary algorithms; in silico evolution; machine learning; materials design and development; neural networks; Introduction There is still not a clear understanding of

• characteristics of living entities can now be simulated in silico and in the laboratory. We are now experiencing another type of evolution, driven by human intellect, that is modifying the way life evolves now and in the future. Figure 1 illustrates how modification and adaptation of organisms, initially arising

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• produced by a Streptomyces strain collected from deep sea water of the Toyama Bay, Japan. In order to get insight into the construction of the above-mentioned unusual structures, we performed an in silico analysis of the biosynthetic genes of 1 through draft genome sequencing and proposed its biosynthetic

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• in self-optimisation and model-development frameworks is not well documented in the literature. Very recently we have shown that a priori knowledge in the form of density functional theory level (DFT) mechanistic calculations can be used to propose process models and to perform in silico design of

• silico training of the smart DoE algorithm for target optimisation. Thus, the final parameter values in Table 3 were accepted and used in the model employed for the subsequent in silico target optimisation steps. Improvement of process conditions using an a priori model and in silico optimisation Access

• was used as an input to the process model. Upon reaching the targets in silico after a number of optimisation iterations, the successful input conditions were verified experimentally, to confirm the predictions. The in silico results for the optimisation target cost and yields are shown in Figure 4

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• deprotonation by His257 [23]. Our results may also partially explain the potent inhibition of a PqsD inhibitor described in the literature which was discovered in silico and had been equipped with an α-chloroacetyl group [24]. Inhibition of PqsD has been proposed as promising antivirulence strategy leading to

• disruption of AQ signaling and thereby to global down-regulation of virulence factor production [11]. Consequently, PqsD has become a highly attractive target and a great amount of work pioneered by the Hartmann group has resulted in inhibitor discovery using a combination of in vitro assay, in silico

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• requirements of the monomers to be recognised and incorporated to form the product [15][16]. In silico tools to identify the nonribosomal code, namely PKS/NRPS Analysis [17] and NRPSpredictor2 [18], are often accurate for the analysis of bacterial NRPSs. Yet, in our case, none retrieved any result after the

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery

• complementary approach to HTS is the use of virtual (i.e., in silico) HTS. Computer-aided drug discovery and design not only reduces the costs associated with drug discovery by ensuring that best possible lead compound enters animal studies, but it may also reduce the time it takes for a drug to reach the

• scale in silico screening of drug molecules in databases of small molecule compounds for a target of interest. Here a target is “screened” against a library of drug-like molecules and binding affinities of the ligands to the target are estimated using the scoring functions described previously. In

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• metabolites. A most unusual structural type is represented by salimabromide from Enhygromyxa salina. In silico analyses were carried out on the available genome sequences of four bacterial members of the Nannocystineae, revealing the biosynthetic potential of these bacteria. Keywords: Enhygromyxa; genome

• genome mining. Thus, knowledge derived from bioinformatic analysis of microbial genomes paved the way to gain detailed insights into bacterial secondary metabolism. Since then, in silico methods for genome mining have enormously advanced and effective experimental approaches for connecting genomic and

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

Correction: Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 608–610, doi:10.3762/bjoc.12.59

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• ) [12]. As a starting structure for our in silico study, we focused on the latter one (PDB code: 3CPW). This crystal structure was determined in the presence of CCA-N-acetylphenylalanine (CCA-N-Phe), an analogue of the portion of aminoacyl and peptidyl tRNAs interacting most strongly with the 50S

• force field method evaluation is therefore a prerequisite for any meaningful in silico study, especially of processes that involve molecular recognition by DNA/RNA hosts [26]. Though there are many success stories in the literature, it is not all it's cracked up to be in the euphoric 1990s, when

• , focusing on the realistic description of all enthalpic contributions. Since the whole ribosomal system is by far too complex for any systematic all atom in silico study, we – in a first step – constructed a truncated model of the ribosome, followed by a thorough conformational search of Linezolid and its

Chromatographically separable rotamers of an unhindered amide

• Mario Geffe,
• Lars Andernach,
• Oliver Trapp and
• Till Opatz

Beilstein J. Org. Chem. 2014, 10, 701–706, doi:10.3762/bjoc.10.63

• analysis. Computational studies The rotational barrier was also studied in silico. Therefore, a conformational analysis of 4 was performed using the systematic algorithm to search conformers as implemented in Spartan’10 with the semi-empirical PM6 level of theory [17][18]. All 2111 resulting conformers

• . While in their case only a small energy difference between the E- and the Z-ground states was predicted in silico and confirmed experimentally, our DFT results deviate more significantly from the HPLC and NMR data which show the E-form and not the Z-form to be lower in energy by 0.6–0.8 kJ/mol. The