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

• and their role in drug discovery pipeline are well reviewed in literature [22][23][24][25]. Several methods have been used for protein structure prediction including homology modeling [26][27], threading approaches [28], and ab initio folding [29][30]. Several computational protein structure

• fold recognition [54]. Ab initio (de novo) modeling Ab initio or de novo modeling is employed when there is no sufficiently homologous structure to use comparative modeling. De novo protein modeling does not rely on a template structure. It models the target structure solely based on the sequence. Ab

• represent the side chains. Another step follows to refine this centroid-based structure using an all-atom refinement function in order to relax the structure. Rosetta protein structure prediction methods have shown successes in CASP experiments [56]. Ab initio structure prediction server QUARK, developed by

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed. Keywords: enzymatic glycosylation; PM3 and ab initio calculations

• tautomers was established [44][45][46][47]. We have analyzed the electronic structures of 2,4-diketo and regioisomeric oxo/thioxo tautomers of uracil, 4-thiouracil and 2-thiouracil, as well as their 4(2)-enol(mercapto) forms by the ab initio method (6-31G** level; basic set of parameters). We found that oxo

• and (E)-5-(2-bromovinyl)uracil was evaluated by a geometry optimization employing the ab initio method and data are presented in Figure 8. These data suggest that the structure of the catalytically competent substrate-enzyme complex cannot accommodate spatially dispersed bases 15 and 16 in a rather

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• formation of 109, on the other hand, the steric hindrance was greatly reduced, and consequently no complete regioselectivity was observed. These results were supported by ab initio [HF/6-31G(d)] and density functional theory [B3 LYP/6-31G(d)] calculations. The use of a copper(I) species, without a

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• (ca. 5%) of 1,4-DHQ 22 in addition to 21. Ab initio simulation of 22 (Figure 2) indicated that the enamine functionality causes a flattening of the dihydroquinoline ring to give a more planar, quinoline-like structure. We were intrigued by the result of these stereoelectronic and conformational

• 21 and 22 using typical Miyaura borylation conditions (Scheme 10) [32]. Both were highly crystalline compounds, and comparison of the two crystal structures (Figure 4) highlighted the more planar structure of 30 as a result of the enamine function, as predicted by ab initio methods in Figure 2

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• capable of ab initio or density functional theory (DFT) calculations is used to calculate either (1) force constants (via frequency calculation) along the trajectory, either at every point or in periodic increments, or (2) the gradient of the potential energy, depending on the specific integrator chosen

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated β-cyclodextrins: models for cyclodextrin–steroid interaction

• Mino R. Caira,
• Susan A. Bourne,
• Halima Samsodien and
• Vincent J. Smith

Beilstein J. Org. Chem. 2015, 11, 2616–2630, doi:10.3762/bjoc.11.281

• Crystallographic Database [16], structure solution by isomorphous replacement was not possible. Both crystal structures were therefore solved ab initio by direct methods using the program SHELXD [22]. Model development involved successive difference Fourier syntheses and iterative refinement by the full-matrix

• isostructural counterparts [16], their structures were solved using ab initio direct methods (program SHELXD [22]) and their refinement by full-matrix least-squares followed with program SHELXH-97 [22] operating under the X-Seed interface [32]. For the DIMEB·2ME structure, with a single complex formula unit

Towards inhibitors of glycosyltransferases: A novel approach to the synthesis of 3-acetamido-3-deoxy-D-psicofuranose derivatives

• Maroš Bella,
• Miroslav Koóš and
• Chun-Hung Lin

Beilstein J. Org. Chem. 2015, 11, 1547–1552, doi:10.3762/bjoc.11.170

• carbohydrate substrates [9][16]. Investigations of the catalytic mechanism of inverting glycosyltransferases [18] and N-acetylglucosaminyltransferase I [19] by employing ab initio calculations resulted in the design of inhibitors based on carbohydrate mimetics that simulate the transition state of the

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

• Mohamed Yacine Ameur Messaoud,
• Ghenia Bentabed-Ababsa,
• Madani Hedidi,
• Aïcha Derdour,
• Floris Chevallier,
• Yury S. Halauko,
• Oleg A. Ivashkevich,
• Vadim E. Matulis,
• Laurent Picot,
• Valérie Thiéry,
• Thierry Roisnel,
• Vincent Dorcet and
• Florence Mongin

Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160

• , Figure 4, see Supporting Information File 2). Computational aspects There is a lack of data on the acidity of N-substituted pyrroles and indoles in the literature. NH acidity of unsubstituted pyrrole and indole in DMSO was measured by Bordwell [48] and computed by means of semi-empirical AM1 [49] and ab

• initio methods [50]. The pKa values for N-methylindole, N-methylpyrrole and N-(dimethylamino)pyrrole as CH acids in THF were experimentally determined by Fraser et al [51]. The latter are more related to our goals and were found to be in good agreement with those computed within the DFT framework

Why base-catalyzed isomerization of N-propargyl amides yields mostly allenamides rather than ynamides

• Armando Navarro-Vázquez

Beilstein J. Org. Chem. 2015, 11, 1441–1446, doi:10.3762/bjoc.11.156

• support of ab initio and DFT computations, this work shows that observed results can be explained by assuming an exchange equilibrium between energetically close N-propargyl, allenyl and N-alkynyl forms and that the reaction outcome correlates to a particular equilibrium mixture. Due to the very small

• for the corresponding isomers for a selected combination of starting amides or carbamates and a final urea example (Figure 1) were computed using ab initio and DFT methods. Results and Discussion Computational procedures It is known that ab initio prediction of cumulene–polyynes isomerization energies

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

Single-molecule conductance of a chemically modified, π-extended tetrathiafulvalene and its charge-transfer complex with F₄TCNQ

• Raúl García,
• M. Ángeles Herranz,
• Edmund Leary,
• M. Teresa González,
• Gabino Rubio Bollinger,
• Marius Bürkle,
• Linda A. Zotti,
• Yoshihiro Asai,
• Fabian Pauly,
• Juan Carlos Cuevas,
• Nicolás Agraït and
• Nazario Martín

Beilstein J. Org. Chem. 2015, 11, 1068–1078, doi:10.3762/bjoc.11.120

• experimental resolution, based on the value we measure for the CT complex. Ab initio calculations To gain insight into the conduction mechanism of compound 5, we performed theoretical calculations based on a combination of density functional theory (DFT) and Green’s functions techniques within the framework of

Mechanical stability of bivalent transition metal complexes analyzed by single-molecule force spectroscopy

• Manuel Gensler,
• Christian Eidamshaus,
• Maurice Taszarek,
• Hans-Ulrich Reissig and
• Jürgen P. Rabe

Beilstein J. Org. Chem. 2015, 11, 817–827, doi:10.3762/bjoc.11.91

• aqueous solutions of CuSO4 (Figure 1). As a result, rupture forces of both valencies were similar. Combining DFS with ab-initio calculations we suggested a stepwise bond-rupture including a hydrogen-bound intermediate. Thus in our system the bivalent effect did not increase the mechanical stability, but

• single-molecular level. For example, a Pd2+ pincer complex with two different pyridine ligands shows rupture lengths around 0.2 nm in DMSO [28]. Using ab-initio calculations we could show that a hydrogen-bound intermediate state stabilizes the interaction over a longer distance [27]. In this case, a

• in aqueous solution. The octahedral conformation of 1 with additional water ligands was suggested by ab-initio calculations [27]. For 2a a quasi-octahedral configuration was calculated with only three water ligands per Cu2+ due to steric reasons [27]. Schemes for 2b and 2c are suggested accordingly

Synthesis and characterization of a new photoinduced switchable β-cyclodextrin dimer

• Florian Hamon,
• Claire Blaszkiewicz,
• Marie Buchotte,
• Estelle Banaszak-Léonard,
• Hervé Bricout,
• Sébastien Tilloy,
• Eric Monflier,
• Christine Cézard,
• Laurent Bouteiller,
• Christophe Len and
• Florence Djedaini-Pilard

Beilstein J. Org. Chem. 2014, 10, 2874–2885, doi:10.3762/bjoc.10.304

• high solubility in water. The photoisomerization properties were studied by UV–vis and HPLC and supported by ab initio calculations. The cis/trans ratio of AZO-CDim 1 is 7:93 without irradiation and 37:63 after 120 min of irradiation at 365 nm; the reaction is reversible after irradiation at 254 nm

• times without causing side effects, as shown in Figure 3. Ab initio calculations were also performed but the cis/trans transition was not observed since molecular modeling methods are unable to break bonds. In order to collect data on this phenomenon, the two configurations of the system had to be taken

• into account separately. Thus, ab initio calculations were performed on the two configurations of the azobenzene linker, the so-called 4,4’-bis(N-methylcarboxamide)azobenzene linker, to determine the structures of minimal energy (Figure 4a and Figure 4b). Once optimized, the measured C4–C4’ distances

Specific DNA duplex formation at an artificial lipid bilayer: fluorescence microscopy after Sybr Green I staining

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2014, 10, 2307–2321, doi:10.3762/bjoc.10.240

• values of ≈5 × 104 kHz. Further experiments concerning a multiple compartment chamber with a common aqueous sub-phase, as well as a thermostated device for a suppression of nonspecific base pairing are underway [15]. Moreover, ab initio molecular-dynamics- (AIMD)- and ab initio Monte-Carlo- (AIMC

Supercritical carbon dioxide: a solvent like no other

• Jocelyn Peach and
• Julian Eastoe

Beilstein J. Org. Chem. 2014, 10, 1878–1895, doi:10.3762/bjoc.10.196

• . have a large body of both practical and theoretical work around polymer solubility in carbon dioxide [84]. The first reported use of ab initio modelling to design oxygenated hydrocarbon polymers for use in CO2 was in 2009, where one oligomer and two polymers were synthesised and found to be soluble in

• CO2 after ab initio predictions. The molecules OAO, PVMME and PVMEE were derived from the smaller CO2-philic moieties MIA, 2MME and 2MEE. It is hoped that other macromolecules could also be designed based on these moieties in time (Figure 4). Unfortunately, ab initio modelling can be quite limiting as

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

• Ilja V. Fateev,
• Konstantin V. Antonov,
• Irina D. Konstantinova,
• Tatyana I. Muravyova,
• Frank Seela,
• Roman S. Esipov,
• Anatoly I. Miroshnikov and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2014, 10, 1657–1669, doi:10.3762/bjoc.10.173

• ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot

• ), their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a; Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the

• stereochemistry of both anomers as dilithium salts was analyzed by the ab initio calculations (3-21G; total charge equal to zero; Polak–Ribiere conjugate gradient) employing AMBER force field geometry optimization as a starting approximation. Two structures with the C-3-exo conformation of the pentofuranose ring

Substitution effect and effect of axle’s flexibility at (pseudo-)rotaxanes

• Friedrich Malberg,
• Jan Gerit Brandenburg,
• Werner Reckien,
• Oldamur Hollóczki,
• Stefan Grimme and
• Barbara Kirchner

Beilstein J. Org. Chem. 2014, 10, 1299–1307, doi:10.3762/bjoc.10.131

• (standard values were chosen here) was set to 1.3 Å. The Hammett parameters are taken from [43]. Computational details for periodic calculation The periodic calculations were carried out with the Vienna ab-initio simulation package VASP 5.3 [44][45]. We utilized the GGA functional PBE [46] in combination

Theoretical studies on the intramolecular cyclization of 2,4,6-t-Bu₃C₆H₂P=C: and effects of conjugation between the P=C and aromatic moieties

• Masaaki Yoshifuji and
• Shigekazu Ito

Beilstein J. Org. Chem. 2014, 10, 1032–1036, doi:10.3762/bjoc.10.103

• Abstract The intramolecular C–H insertion of the Mes*-substituted phosphanylidenecarbene [Mes*P=C:] (Mes* = 2,4,6-t-Bu3C6H2) and physicochemical properties of the cyclized product, 6,8-di-tert-butyl-3,4-dihydro-4,4-dimethyl-1-phosphanaphthalene were studied based on ab initio calculations. Whereas the

• calculation data. Ab initio and DFT calculations were carried out with the Gaussian 09 program package [18]. Structures of 1 in the singlet state and 2 were optimized at the MP2(Full)/6-31G(d) level, and subsequently employed for calculation of the transition state. DFT methods were avoided in this

• conclusion, the chemistry of the intramolecular C–H insertion of phosphanylidenecarbene 1 affording 2 was studied by ab initio and DFT calculations. The intramolecular cyclization requires an activation energy, whereas the phosphorus version of the FBW rearrangement proceeded without an energetic barrier

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• investigated the reactivity of mono- and difluoroaziridines 2 and 3 (Figure 1) [15][16]. As well as the enhanced reactivity that 2 and 3 both show towards nucleophilic ring opening, there is an additional subtlety regarding the regioselectivity. While ab initio calculations predict that both 2 and 3 should

True and masked three-coordinate T-shaped platinum(II) intermediates

• Manuel A. Ortuño,
• Salvador Conejero and
• Agustí Lledós

Beilstein J. Org. Chem. 2013, 9, 1352–1382, doi:10.3762/bjoc.9.153

• at work in solution. Recently, ab initio molecular dynamics (AIMD) simulations of some representative T-shaped Pt(II) complexes (T5b, A2b and A11a), performed in explicit dichloromethane solvent, have provided a detailed description of the mechanism by which the equivalence of signals takes place

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• readily interconvertable 12 and 14. We found this controversy in the isolation and total synthesis papers an interesting one that deserves further investigations. Consequently, we performed ab initio calculations on 12 and 14 to gain insight into their relative thermodynamic stability. Models of the most

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

• Magnus Liljenberg,
• Tore Brinck,
• Tobias Rein and
• Mats Svensson

Beilstein J. Org. Chem. 2013, 9, 791–799, doi:10.3762/bjoc.9.90

• that the B3LYP functional predicts a concerted reaction in some cases, including an intramolecular SNAr reaction, where the M06-2X functional and high level ab initio theory show that the reaction is stepwise [33]. In light of these observations, we investigated the potential energy surface also at the

Ring opening of 2-aza-3-borabicyclo[2.2.0]hex-5-ene, the Dewar form of 1,2-dihydro-1,2-azaborine: stepwise versus concerted mechanisms

• Holger F. Bettinger and
• Otto Hauler

Beilstein J. Org. Chem. 2013, 9, 761–766, doi:10.3762/bjoc.9.86

• isomerisation reaction, 22 kcal mol−1, should be high enough for an experimental observation in solution. However, in solution the dimerisation of 3 is computed to have a very low barrier (3 kcal mol−1), and thus 3 is expected to be a short-lived reactive intermediate. Keywords: ab initio; azaborine; BN

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

• Martina Bonsignore,
• Maurizio Benaglia,
• Laura Raimondi,
• Manuel Orlandi and
• Giuseppe Celentano

Beilstein J. Org. Chem. 2013, 9, 633–640, doi:10.3762/bjoc.9.71

• structures leading to the formation of the R and S products, respectively, were optimized to the relative TSs with HF/3-21G ab-initio methods [30]. After vibrational characterization of these structures (both with only one imaginary frequency), they were fully re-optimized with DFT methods [30]: optimization

• below. Force field conformational analysis was performed with the Schroedinger suite MacroModel. Ab initio and DFT calculations were performed with Gaussian09 [33]. Frequency calculations allowed for characterization as such of the transition structures and for calculation of ZPE-corrected free energies