Reverse-docking as a computational tool for the study of asymmetric organocatalysis

A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment. Clear energetic trends emerged from docking the catalyst to both enantiomers of all six azidation TS models of this study. Structural analysis of the most favorable pose suggests a mechanism for enantioselective catalysis that is consistent with principles of molecular recognition, catalysis, and experimental data.     

Increased Affinity of 2′‐O‐(2‐Methoxyethyl)‐Modified Oligonucleotides to RNA through Conjugation of Spermine at Cytidines

Structural modification at the 2′‐O‐position of riboses in oligonucleotide therapeutics is of critical importance for their use as drugs. To date, the methoxyethyl (MOE) substituent is the most important and features in dozens of antisense oligonucleotides that have been tested in clinical trials. Yet, the search for new improved modifications continues in a quest for increased oligonucleotide potency, improved transport in vivo and favorable metabolism. Recently, we described how the conjugation of spermine groups to pyrimidines in oligonucleotides vastly increases their affinity for complementary RNAs through accelerated binding kinetics. Here we describe how spermines can be linked to the exocyclic amino groups of cytidines in MOE‐oligonucleotides employing a straightforward ‘convertible nucleoside approach’ during solid phase synthesis. Singly‐ or doubly‐modified oligonucleotides show greatly enhanced affinity for complementary RNA, with potential for a new generation of MOE‐based oligonucleotide drugs.     

Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

Summary The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex^®) and rofecoxib (Vioxx^®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.     

Synthesis,analytical and spectral characterization for new VO (II)-triazole complexes; conformational study beside MOE docking simulation features

New triazole-derivatives were synthesized and characterized (spectral, analytical and conformational). After that, the new derivatives were coordinated with VO (II) atom to prepare new series of complexes. Distorted octahedral and square-pyramidal geometries, were the geometries suggested based on UV- Vis and ESR spectra. A neutral poly-dentate mode of bonding was proposed by 1:1 (M:L), for all complexes. TGA study supports the molecular formula of VO (II) complexes as well as, mass spectral-analysis that executed for examples. The isotropic, anisotropic, molecular orbital and Hamiltonian parameters were estimated upon ESR spectra, for selected complexes. XRD patterns were executed for three complexes, two among appeared with particulate-sizes in nanometer-range. Conformational study was executed for all synthesizes applying RTD-B3LYP-FC method. Essential physical parameters were estimated and discussed. MOE-docking that considered a bright part, was performed over all compounds towards 3s7s and 5jm5, as functional tumor proteins. The docking interaction parameters, introduced strongly some synthesizes to be anti-tumor agents.     

The MOE Modification of RNA: Origins and Widescale Impact on the Oligonucleotide Therapeutics Field

In an article published by Helvetica Chimica Acta in 1995, chemist P. Martin describes the synthesis of 2′-O-alkylated ribonucleosides for use in therapeutic antisense oligonucleotides (ASOs). This work was motivated by the need for a modified ribose structure that was compatible with solid-phase synthesis protocols and that, when incorporated into an oligonucleotide, would render it resistant to nucleases without attenuating its ability to hybridize to a complementary RNA target. Martin described a robust route to 2′-O-alkylribonucleosides in which the ribose 2′-OH group is substituted with 2′-ethylene glycol derivatives. Oligonucleotides containing these modifications displayed überraschende Eigenschaften – ‘surprising properties’ – notably, higher affinity and specificity for RNA substrates and greater stability to nucleases relative to their unmodified counterparts. Today, the 2′-ethylene glycol modification is universally known in the field as the 2′-O-methoxyethyl (MOE) modification. The chemistry features in four ASO drugs and many others in clinical trials. Here, we 1) summarize the synthesis of the MOE-modified ribose; 2) outline the properties of MOE-modified oligonucleotides as reported in Martin’s article; 3) highlight the first approved MOE-modified ASO drugs, mipomersen and nusinersen; and 4) survey MOE-modified ASOs in clinical development. In the outlook, we put these developments into context and consider future possibilities for the MOE modification.     

Synthesis,Molecular Docking Studies,and Anticonvulsant Evaluation of Novel bis‐Phenylhydrazones against Chemically induced Seizures in Mice

A series of novel bis‐phenylhydrazones were synthesized by the condensation of dialdehydes with phenylhydrazine to evaluate them for their anticonvulsant activity. Efficacy of newly synthesized compounds against pentylenetetrazole (PTZ )‐induced, strychnine‐induced, and picrotoxin‐induced convulsions was tested after administration of these compounds to albino mice via the oral route. All the five tested compounds showed anticonvulsant activity against strychnine‐induced and picrotoxin‐induced convulsions in a dose‐dependent manner. However, the effect was more significant against PTZ ‐induced convulsions. Behavioral pattern studies on mice suggested that these compounds are less neurotoxic compared to phenytoin. Molecular docking studies were carried out to correlate the experimental and theoretical results. It was concluded that these compounds exerted their anticonvulsant effect through the modification of the function of GABA receptor‐mediated chloride channels. Molecular docking studies revealed a good correlation, which indicated that in silico studies could provide an alternate tool for the identification and design of more potent anticonvulsant agents.     

Synthesis and Antimicrobial Activity Screening of Piperazines Bearing N,N′-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors

A new N,N′-disubstituted piperazine conjugated with 1,3,4-thiadiazole and 1,2,4-triazole was prepared and the chemical structures were identified by IR, NMR and elemental analysis. All the prepared compounds were tested for their antimicrobial activity. The antimicrobial results indicated that the tested compounds showed significant antibacterial activity against gram-negative strains, especially E. coli, relative to gram-positive bacteria. Docking analysis was performed to support the biological results; binding modes with the active site of enoyl reductase amino acids from E. coli showed very good scores, ranging from −6.1090 to −9.6184 kcal/mol. Correlation analysis was performed for the inhibition zone (nm) and the docking score.     

New NIR-II dyes without a benzobisthiadiazole core

Compared to the well-studied NIR-I small-molecule fluorophores, the structures of NIR-II fluorophores are scarce yet. Most NIR-II fluorophores are composed of D-A-D structures. It is essential to search for the new structures of NIR-II fluorophores to enlarge the field of NIR-II dyes.     

Synthesis of novel VO (II)‐thaizole complexes; spectral,conformational characterization,MOE‐docking and genotoxicity

New VO (II)‐thaizolyl hydrazine complexes were synthesized and characterized by analytical, spectral and theoretical techniques. Bi‐nuclear complexes were suggested for all synthesizes upon neutral poly‐dentate mode of bonding. UV–Vis and EPR spectra, proposed two structural geometries as, square‐planer and octahedral. TGA confirmed the contribution of solvent molecules through physical and/or coordinate‐bonding. XRD parameters calculated, displayed outstanding nanometer‐sizes for all nano‐crystalline compounds, which suffering slight imperfections. Also, SEM images showed, spherical‐shape that observed for most topographic particulates. Conformational study executed for all new synthesizes, demonstrated their optimized structural‐forms. Furthermore, important physical parameters were computed that predict essential characteristics as, biological efficiency. Predictable parameters as softness and electrophilicity, point to priority of VO (II)‐4d complex. Genotoxic study, was already examined, for all new synthesizes, against CT‐DNA and displayed complete deterioration for DNA, by influence of most tested compounds. Moreover, MOE‐docking technique, was executed against receptors of Y‐family DNA‐polymerase (4irk) and Key‐Enzyme Linking‐Metabolic Inflammation (4cyf). This docking study displayed the following ascending order; VO (II)‐4c,4irk ? VO (II)‐4d,4cyf ? VO (II)‐4c, 4cyf ? VO (II)‐4b, 4cyf, based on scoring‐energy values. This study concluded with promising prediction of these complexes in relation to DNA‐polymerase as well as inflammation enzyme that compared with known anti‐inflammatory drug (meloxicam).     

Resistive switching behavior and mechanism of room-temperature-fabricated flexible Al/TiS2-PVP/ITO/PET memory devices

The mixture of two-dimensional (2D) TiS₂ nanoflakes and polyvinylpyrrolidone (PVP) exhibits a nonvolatile, bipolar resistive switching behavior with a low resistance state (LRS)/high resistance state (HRS) current ratio of ～10² in the devices with a flexible Al/TiS₂-PVP/indium tin oxide (ITO)/polyethylene terephthalate (PET) structure. The polymer-assistant liquid-phase exfoliation of 2D nanoflakes from TiS₂ bulk material is processed in low-boiling solvent. And the fabrication process of these devices is performed entirely at room temperature. Such an energy-saving and scalable production process indicates a huge potential of large-scale industrial application. The AFM and TEM characterizations showed that the exfoliated 2D TiS₂ are flakes at micrometer scale with a layer-number of mostly 7 or 8. Both the HRS and the LRS can be kept for more than 10⁴ s. The endurance of devices was obtained over 100 direct current (DC) sweeping cycles with remarkable separations between different resistive states. The distributions of writing (set) and erasing (reset) voltages show that set and reset voltages are small (<2 V). Also, the resistive switching characteristics of the devices are stable during 1000 bending cycles. The switching behavior is explained by the thinning and recovery of Schottky barriers within devices.