Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• details see Supporting Information File 1). The Db nucleobases were individually incorporated into the PNA model oligonucleotide and subjected to 50 ns unrestricted Desmond molecular dynamics. Pictures from the molecular dynamics simulations shown in Figure 7 represent the conformation of the PNA bases

• from glutaric anhydride [30]. In fact, molecular dynamics simulations did confirm that the amide carbonyl of the linker forms a stable H-bond to the amino group of C (Figure 7C). Since the distal guanosine in the C–G base pair is a mismatch with the isoorotic acid binding moiety, the isoorotamide

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• more membrane perturbation compared to the axle alone, in agreement with our previous molecular dynamics simulations, which highlight the importance of the macrocycle to modulate lipid packing [15]. As cholesterol content increased, sulforhodamine B release progressively decreased, consistent with the

• previous molecular dynamics simulations of rotaxane 1 in POPC bilayers, a major component of EYPC [16], showed that rotaxane 1 disrupts lipid packing and promotes water accumulation within the bilayer [15]. These effects enhance membrane permeability to hydrophilic molecules such as sulforhodamine B. The

• simulations also suggest that the macrocycle of rotaxane 1-E tends to reside closer to the lipid–water interface, promoting more water accumulation than 1-Z, whose macrocycle positions deeper within the bilayer. This difference in localization likely arises from the substantial change in size and polarity of

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• lipid membrane, leading to reversible changes in giant lipid vesicles. In the trans isomer, the membrane tension decreased, resulting in deformation and pronounced membrane undulations. Isomerization to the cis form increased membrane tension, causing vesicle contraction. Molecular dynamics simulations

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• positioned on the opposite lobe of the protein, as compared to lysine 241 of CLK3 (N-lobe for DYRK1A vs C-lobe for CLK3), but the docking experiment showed that a 180° rotation of the benzoic acid allowed the inhibitor to interact with lysine 175. In addition to molecular simulations, this salt bridge is

A chiral LC–MS strategy for stereochemical assignment of natural products sharing a 3-methylpent-4-en-2-ol moiety in their terminal structures

• Rei Suo,
• Raku Irie,
• Hinako Nakayama,
• Yuta Ishimaru,
• Yuya Akama,
• Masato Oikawa and
• Shiro Itoi

Beilstein J. Org. Chem. 2025, 21, 2243–2249, doi:10.3762/bjoc.21.171

• analysis, and computational methods have been widely used. For example, the absolute configuration of chaetomugilin B [19] was determined by X-ray crystallography, while that of capsulactone (1) was established through density functional theory (DFT)-based simulations of NMR chemical shifts and electronic

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• synthetic organic chemists. We report a computational study on the mechanism of diazabicyclo[2.2.1]heptenes to address long standing mechanistic questions. Indeed, the mechanism of these reactions has been disputed for over six decades. We employed non-adiabatic molecular dynamics (NAMD) simulations

• two possible S1/S0-MECIs. Our dynamics simulations illustrate that inversion begins in the excited state immediately after the first σCN bond breaks. This inversion is driven by the atomic momenta acquired after the bond breaks. These dynamical effects promote the formation of the inverted housane

• molecular dynamics (NAMD) simulations of a series of diazabicyclo[2.1.1]hexenes. The minimum energy path showed stepwise σCN bond breaking and led directly to a minimum energy crossing point, corresponding to the inversion product. We also performed NAMD simulations on halogenated derivatives to test the

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• Quantumwise ATK-classical is devised for geometry optimization. The graphite (previously optimized) was kept fixed during the simulations, and the molecular geometry was fully optimized. Parameter set: ReaxFF-CHO-2008 [32]. A force tolerance of 0.001 eV/Å, stress tolerance of 0.001 eV/Å, and a maximum step

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• reactivity of compounds. This trend aligns with the increasing reactivity order: 5d < 5a ≈ 5b < 5e < 5c. Molecular docking simulations provided insights into the binding interactions of these compounds with the inducible nitric oxide synthase (iNOS) enzyme. Compound 5e exhibited the strongest binding

• . The docking algorithm used was the Triangle Matcher placement method, which generates initial poses by aligning ligand atoms to complementary receptor atoms. Molecular docking simulations were performed using the MOE software suite [46] to evaluate the binding activities of the newly synthesized

Hydrogen-bonded macrocycle-mediated dimerization for orthogonal supramolecular polymerization

• Wentao Yu,
• Zhiyao Yang,
• Chengkan Yu,
• Xiaowei Li and
• Lihua Yuan

Beilstein J. Org. Chem. 2025, 21, 179–188, doi:10.3762/bjoc.21.10

• formation of 2:2 complex came from ESIMS experiments. The mass spectra recorded for a 1:1 mixture of H1 and G2 showed a multicharged pseudomolecular ion peak corresponding to [H12 + G22 + H+ − 2PF6−]3+, and the isotope patterns were in good agreement with theoretical simulations (Figure S12, Supporting

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• calculated distance from the NOE cross peaks is roughly 2 Å for both contacts. We know that the triazole units can rotate by some degree at ambient temperature based on previous investigations [87]. Thus, dynamic tilting up and downwards of the triazole groups is expected. Molecular dynamics simulations (xTB

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• confirm that the relaxed structures correspond to local minima (no imaginary frequencies) or transition states (one imaginary frequency). The reaction simulations were run in chloroform using the “Solvation Model based on Density” (SMD) [36] at 273.0 K to reproduce the most commonly used experimental

• initial study, it can be concluded that the mechanism for our system proceeds according to mechanism two. The following simulations were performed on this conclusion. Regioselectivity PO exhibits two distinct electrophilic sites, which can be subject to nucleophilic attack (Figure 2B). Thus, the

Deciphering the mechanism of γ-cyclodextrin’s hydrophobic cavity hydration: an integrated experimental and theoretical study

• Stiliyana Pereva,
• Stefan Dobrev,
• Tsveta Sarafska,
• Valya Nikolova,
• Silvia Angelova,
• Tony Spassov and
• Todor Dudev

Beilstein J. Org. Chem. 2024, 20, 2635–2643, doi:10.3762/bjoc.20.221

• thermochemistry (and thermodynamic values). To assess the thermodynamic feasibility of the complex formation reaction, we used the enthalpy change, ΔH, when going from reagents to products. The SMD [29] model is used to incorporate the effects of water as a solvent in the molecular simulations – single point

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• – allowing for the generation of extensive data through large-scale simulations – chemical reactions pose a much greater difficulty for accurate simulation. The development of systematic theoretical calculations to model correlations between reaction yields and various substrates and catalysts requires

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• , both in free state and in complex with proteins, also with reference to the principles, methodologies, and applications of all-atom molecular dynamics simulations. Herein, we focused on the programs that are generally employed for preparing protein and glycan input files to execute molecular dynamics

• simulations and analyse the corresponding results. The presented computational toolbox represents a valuable resource for researchers studying protein–glycan interactions and incorporates advanced computational methods for building, visualising and predicting protein/glycan structures, modelling protein

• tools, designed to guide the structural and conformational elucidation process, and on the application of molecular dynamic simulations to the study of proteins and glycans in free and bound states. Detailed protocols and methods for protein and glycan modelling are extensively described and links to

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• antiproliferative activity when tested against a panel of different tumorous cells (GI50 = 2.0–11 μM). Docking simulations revealed that spiromorpholinone 149 could act as an aromatase inhibitor [63]. Spirotriazine steroids Bakhotmah and Abdel-Rahman developed steroidal spiropyrazolotriazine derivatives 152–154

Novel route to enhance the thermo-optical performance of bicyclic diene photoswitches for solar thermal batteries

• Akanksha Ashok Sangolkar,
• Rama Krishna Kadiyam and
• Ravinder Pawar

Beilstein J. Org. Chem. 2024, 20, 1053–1068, doi:10.3762/bjoc.20.93

• generated. The thermal stability and reversibility of the photoswitching cycle of the type-IIa photoswitch was analyzed using the ab initio molecular dynamics (AIMD) simulations. The proposed mechanism for the thermal back conversion and undesired thermal degradation of the photoproduct is illustrated in

• whose unsaturated bridge was extended using the –(CO)–, –CH2–, and –NH– show thermodynamic feasibility for reversible photoswitching. Furthermore, the thermal reversibility of the photoswitching process has been validated by AIMD simulations initiated using the biradicaloid TS structure of the IIa

• photoswitch. The variation in α, β, and γ-bond distances calculated during the AIMD dynamic trajectory is displayed in Figure 8. It is apparent from the figure that the α and γ-bond distances increase during the course of the simulations whereas the β distance almost remained constant. This signifies that

Spatial arrangements of cyclodextrin host–guest complexes in solution studied by ¹³C NMR and molecular modelling

• Konstantin Lebedinskiy,
• Ivan Barvík,
• Zdeněk Tošner,
• Ivana Císařová,
• Jindřich Jindřich and
• Radim Hrdina

Beilstein J. Org. Chem. 2024, 20, 331–335, doi:10.3762/bjoc.20.33

• ten classical molecular dynamics (MD) simulations [16] (each lasting 100 ns, Figure 3). Then, we superimposed α-CD structures from different snapshots of each MD run. Further, the 3D densities, showing the spatial distribution of prochiral atoms of ligands (that rotate and wobble towards α-CD), were

• compound 4, we were thus able to select representative conformations of the guest molecule in all types of cyclodextrins (Figure 5) using the spatial densities gained from classical MD simulations. Compounds 1–8 (as hydrochloride salts or free bases), were attempted to co-crystallize with α-, β- and γ

• . The 3D densities show the spatial distribution of prochiral atoms within MD simulations. Studied host–guest complexes and splitting of guests’ prochiral carbons in their 13C NMR spectra. Molecular modelling of the host–guest complexes of compound 4 with α-CD, β-CD and γ-CD. X-ray analysis of the α-CD

Electron-beam-promoted fullerene dimerization in nanotubes: insights from DFT computations

• Laura Abella,
• Gerard Novell-Leruth,
• Josep M. Ricart,
• Josep M. Poblet and
• Antonio Rodríguez-Fortea

Beilstein J. Org. Chem. 2024, 20, 92–100, doi:10.3762/bjoc.20.10

• metadynamics simulations provide hints on structures for the initial steps of the irreversible phase 2 where bond formation and breaking lead to important structural reorganizations within the coalescence process. Keywords: DFT; dimerization; fullerene; molecular dynamics; peapods; Introduction Transmission

• pressures and high temperatures [13][14][15]. We aim to shed light in these reaction mechanisms and energy profiles by using complementary methodologies as standard density functional theory (DFT) calculations and first-principles Car–Parrinello molecular dynamics (CPMD) simulations. Firstly, we have

• the subsequent irreversible C–C fusions occurring in phase 2 are proposed with the help of accelerated Car–Parrinello MD simulations. Results and Discussion Nanotube-C60 interaction: stabilization of the peapod First, we estimated the size of the stabilizing interaction that holds the peapod, that is

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• displayed in Scheme 1. All simulations were performed with COPASI, an open-source software [48]. The second-order rate constants were obtained by fitting the experimental time traces until a fully consistent data set, being valid for all experimental conditions, was established. For X-ray structure analyses

Studying specificity in protein–glycosaminoglycan recognition with umbrella sampling

• Mateusz Marcisz,
• Sebastian Anila,
• Margrethe Gaardløs,
• Martin Zacharias and
• Sergey A. Samsonov

Beilstein J. Org. Chem. 2023, 19, 1933–1946, doi:10.3762/bjoc.19.144

• multipose character of GAG binding and the polarity of the binding poses of these periodic molecules. In the present work, all-atom MD simulations are conducted to study the dynamics of the protein–GAG complexes, and are complemented by free energy analysis. The free energy analysis of the protein–GAG

• sulfate-6 was added to the reducing end of the GAG. The starting binding mode for the cathepsin K complex with chondroitin sulfate corresponded to the 3CE9 complex. Literature data for the sulfate groups [38] and GLYCAM06 [39] force field parameters were used for GAGs in the subsequent MD simulations. A

• 1C4 conformation for the IdoA2S ring was chosen as it was shown to be the essentially dominant conformation in the microsecond scale simulations performed by Sattelle et al. as it is energetically more favorable than the 2SO conformation [40]. Complex preparation The obtained ligands were docked using

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• /23 = 4.6 of the respective monomer 22, which was already best among fullerene monomers. In computational simulations, the positive maximum of the MEP surface next to the amine base was the same for dimer 37 (+13.9 kJ mol−1) and monomer 22 (+13.8 kJ mol−1), supporting that the dramatic increase in

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Phenanthridine–pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme

• Josipa Matić,
• Tana Tandarić,
• Marijana Radić Stojković,
• Filip Šupljika,
• Zrinka Karačić,
• Ana Tomašić Paić,
• Lucija Horvat,
• Robert Vianello and
• Lidija-Marija Tumir

Beilstein J. Org. Chem. 2023, 19, 550–565, doi:10.3762/bjoc.19.40

• in the cell membrane. Keywords: dipeptidyl peptidase enzyme; excimer; molecular dynamics simulations; phenanthridine; polynucleotide; pyrene; Introduction The design of small molecules that can selectively bind and discriminate different biomolecular structures (polynucleotides vs proteins, DNA or

• simulations additionally supported the pronounced hypochromic effect (chapter Computational analysis). Fluorescence spectra Fluorescence emission of Phen-Py-1 and Phen-Py-2 measured at pH 5 and pH 7 (cacodylate buffer, Ic = 0.05 mol dm−3) was linearly dependent on the concentration up to 4 × 10−6 mol dm−3

• molecular dynamics (MD) simulations of different protonation forms of Phen-Py-1 and Phen-Py-2 placed in explicit water solvation, and analyzed structural preferences in the obtained trajectories. In setting up our simulations, we prepared the geometries of unionized Phen-Py-1 and Phen-Py-2 and their