Aromatic Carbon Atoms Research Articles

Cheminformatics-driven prediction of BACE-1 inhibitors: Affinity and molecular mechanism exploration

The β-secretase, sometimes referred to as BACE1 or Asp2, is the enzyme responsible for initiating the production of Aβ by breaking down the amyloid precursor protein. Hence, BACE is a pivotal target for pharmacological intervention aimed at diminishing the production of Aβ in Alzheimer's disease (AD). We did a quantitative structure-activity relationship (QSAR) study on 1235 compounds that had been experimentally reported as BACE-1 inhibitors (Ki) to find the target molecule and structural patterns linked to blocking the BACE-1 receptor. The OECD-recommended genetic algorithm-multiple linear regression (GA-MLR) QSAR model strikes a good balance between being able to make accurate predictions and understanding how things work. It achieves high values for many evaluation metrics, including R2tr = 0.8047, Q2LMO = 0.802, R2ex = 0.805, CCCex = 0.891, Q2-F1=0.801, Q2-F2=0.799, and Q2-F3=0.815. The mechanistic interpretation of QSAR has identified some nitrogen atoms that are required to block beta-secretase and make it less effective at doing its job. A positively charged aromatic carbon atom has a more significant impact on beta-secretase-1 inhibition. The docking study showed that the catalytic dye residues Asp32 and Asp228 become protonated when compound 27 is present, but they stay unprotonated when compound 27 is not present. These rings of pyrazine and pyridine interact hydrophobically with Tyr71 and Ile118 residues, confirming the pharmacophoric features seen in the QSAR data. We examined the stability of both the protein-ligand complex and the apo-protein. The apoprotein had an average gyration radius of 22.13, whereas the protein-ligand complex had an average gyration radius of 22.91. No changes were made to the results from the molecular docking, molecular dynamics (MD) simulation, MMGBSA (Molecular Mechanics Generalized Born Surface Area), or DFT analyses. Therefore, the current work could effectively contribute to the future development of BACE inhibitors in medication design.

Updating Reaction Mechanistic Domains for Skin Sensitization: 1. Nucleophilic Skin Sensitizers.

It has long been recognized that skin sensitizers either are electrophilic or can be activated to electrophilic species. Several nonanimal assays for skin sensitization are based on this premise. In the course of a project to update dermal sensitization thresholds (DST), we found a substantial number of sensitizers, with no electrophilic or pro-electrophilic alerts, that could be simply explained in terms of the sensitizer acting as a nucleophile. In some cases, the nucleophilic center is a sulfur or phosphorus atom, while in others, it is an aromatic carbon atom. For carbon-centered nucleophiles, a quantitative mechanistic model based on a combination of Hammett σ+ and logP values has been derived. This has been applied to rationalize several groups of known sensitizers with no electrophilic or pro-electrophilic alerts, including anacardic acids and cardols, which are known human sensitizers associated with, inter alia, cashew nut oil, mango, and Ginkgo biloba. The possibility of nucleophilic sensitization needs to be considered when evaluating new chemicals for skin sensitization potential and potency by nonanimal assays, particularly those based on the premise that skin sensitization is dependent upon reactions of electrophiles with skin protein-based nucleophiles.

Computational Insights into the Intramolecular Aromatic C-C Coupling Catalyzed by the Cytochrome P450 Enzyme CYP121 from Mycobacterium tuberculosis.

CYP121 is a P450 enzyme that catalyzes the intramolecular C-C coupling of its native substrate, dicyclotyrosine (cYY). According to previous suggestions, when the cosubstrate peracetic acid was used to generate Cpd I, the substrate cYY was suggested to participate in the cleavage of the O-O bond; however, whether cYY is involved in the formation of Cpd I and how two distant aromatic carbon atoms are activated are still unclear. Here, we constructed computational models and performed QM/MM calculations to clarify the reaction mechanism. On the basis of our calculation results, cYY is not involved in the formation of Cpd I, and the C-C coupling reaction starts from hydrogen abstraction. In the second stage, the substrate should first undergo a complex conformational change, leading to two phenolic hydroxyls of cYY close to each other. In the subsequent reaction, the resultant Cpd II again abstracts a hydrogen atom from the proximal tyrosine to generate the diradical intermediate. In addition, the C-C coupling occurs in the active site, but the final aromatization may be a nonenzymatic reaction. In general, the intramolecular C-C coupling requires two basic conditions, including the active site having good flexibility and the substrate itself having a suitable and rotatable skeleton.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

Синтез новых S-производных 4-амино-1,3,5-триазин-2-тиона и их исследование методами ЯМР 1Н, 13С и хромато-масс-спектрометрии

4-Amino-1,3,5-triazine-2-thione 1 interacts with allyl bromide, 2-methyl-3-chloro-1-propene, 2,3-dibromopropene-1, prenyl bromide in DMFA/K2CO3 and with cinnamyl chloride, butenyl bromide in DMFA/NaOH to form 4-allylsulfanyl- 2, 4-(2-methylpropene-2-yl)sulfanyl- 3, 4-(2-bromopropene-2-yl)sulfanyl- 4, 4-(2-methylbutene-2-yl)sulfanyl- 5, 4-cinnamylsulfanyl- 6 and 4-(butene-1-yl)sulfanyl-1,3,5-triazine-2-amines 7, respectively. The structure of compounds 2–7 was studied by 1H NMR, as well as of compounds 5 and 7, in their case including 13C NMR; allyl sulfide 2, prenyl sulfide 5 and butenyl sulfide 7 were also studied using chromatography mass spectrometry. In the 1H NMR spectra of compounds 2–7, the weakest field signal in the range of 8.22–8.30 p.p.m. is the signal of the aromatic proton of the triazine cycle, manifested as a singlet. The signals of protons of the S-CH2 group are observed in a strong field – at 3.10–4.19 p.p.m. – depending on the presence of electron donor or electron acceptor groups in the alkenyl fragment. The protons of the =CH2 group are present only in the structure of sulfides 2–4 and 7; they form two signals in the 1H NMR spectra: one signal at 4.85–5.58 p.p.m., the second at 5.03–6.10 p.p.m. In the 13C NMR spectra of prenyl sulfide 5 and butenyl sulfide 7, the carbon atoms of the S-alkenyl groups resonate in the region of strong fields. In the region of weak fields, the signals of aromatic carbon atoms of the 1,3,5-triazine cycle are observed: 182.32–157.95 p.p.m. In the mass spectra of compounds 2, 5 and 7, the characteristic peaks are [M 15]+ and [M-33]+ peaks, the formation of which is associated with the fragmentation of molecular ions undergoing cleavage of the methyl radical and the •SH radical, respectively. The haloalkyl derivative of the heterocyclic series – 2-chloro-1-(2,2,4-trimethyl-4-phenyl-3,4-dihydroquinoline-1(2H)-yl) ethanoate – in reaction with compound 1 has led to the introduction of a new pharmacophore fragment into the simm-triazine molecule, which contributes to the expansion of the spectrum of potential biological activity of its derivatives.

Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase.

Aldehyde oxidase (AOX) and other related molybdenum-containing enzymes are known to oxidize the C-H bonds of aromatic rings. This process contributes to the metabolism of pharmaceutical compounds and, therefore, is of vital importance to drug pharmacokinetics. The present work describes an automated computational workflow and its use for the prediction of intrinsic reactivity of small aromatic molecules toward a minimal model of the active site of AOX. The workflow is based on quantum chemical transition state searches for the underlying single-step oxidation reaction, where the automated protocol includes identification of unique aromatic C-H bonds, creation of three-dimensional reactant and product complex geometries via a templating approach, search for a transition state, and validation of reaction end points. Conformational search on the reactants, products, and the transition states is performed. The automated procedure has been validated on previously reported transition state barriers and was used to evaluate the intrinsic reactivity of nearly three hundred heterocycles commonly found in approved drug molecules. The intrinsic reactivity of more than 1000 individual aromatic carbon sites is reported. Stereochemical and conformational aspects of the oxidation reaction, which have not been discussed in previous studies, are shown to play important roles in accurate modeling of the oxidation reaction. Observations on structural trends that determine the reactivity are provided and rationalized.

Carbon-to-nitrogen single-atom transmutation of azaarenes.

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means existto make such C-to-N transmutations, typically by parallel synthesis3. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes.

The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen- and sulfur-containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4-(thiophen-2-yl)benzoic acid and 4-(thiophen-3-yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels-Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X-ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4-(thiophen-3-yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4-(Furan-2-yl)benzoic acid was oxidized to 4-(4'-hydroxybutanoyl)benzoic acid using a whole-cell system. This reaction proceeded via a γ-keto-α,β-unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds.

Синтез и электрофильная гетероциклизация 3 алкенилсульфанил-5-фенил-1,2,4-триазинов под дейст-вием иода и брома

Derivatives of 1,2,4-triazine-3-thione are interesting research objects due to a wide range of their applications: drugs, optical substances, precursors for synthesis of new pyridine systems by the Diels-Alder reaction. In the present study, using alkylation of 5-phenyl-2,3-dihydro-1,2,4-triazine-3-thione (1) by 3-chloro-2-methyl-propene, 2,3-dibromopropene-1, 1-bromo-3-methylbut-2-ene and 4-brombut-1-ene, we have obtained 3-(2-methylprop-1-enyl)-, 3-(2-bromoprop-1-enyl)-, 3-prenylsulfanyl- and 3-butenylsulfanyl-5-phenyl-1,2,4-triazines (2a-d), previously unknown. In the 1H NMR spectrum of compound 2b, the shifts of the signal of pro-tons of the SCH2 group and the signal of protons of the vinyl group into a weak field by 0.48 ppm and 0.60 ppm can be observed, compared to the similar signals in the spectrum of 3-allylsulfanyl-5-phenyl-1,2,4-triazine. This may be due to the bromine atom in the allyl fragment. The weakest-field signal in the 13C NMR spectra of compounds 2a-d in the region of 171.86–173.68 ppm refers to the aromatic carbon atom of the triazine cycle in the third position (C-3), bound to a sulfur atom and two nitrogen atoms. New condensed heterocyclic systems of ionic type with a bridging nitrogen atom have been synthesized by electrophilic heterocyclization of methallyl-, bromallyl-, prenyl- and butenyl sulfides 2a-d. At the same time, [1,3]thiazolo[3,2-b][1,2,4]triazinium halides have been obtained by heterocyclization of compounds 2a,2b, and [1,3]thiazino[3,2–b][1,2,4]triazinium halides have been produced by heterocyclization of com-pounds 2c,2d. In the 1H NMR spectra of triazinium halides, a characteristic shift of the signal of the H-6 aromatic proton to the weak field region is observed in comparison with the similar sig-nal in the spectrum of the initial 2a-d sulfides. In the 13C NMR spectra of triazinium halides, there is a shift in the signal of the aromatic carbon atom associated with a sulfur atom and two nitrogen atoms (in the region of 162.56-172.42 ppm), which can be explained by the appearance of a positively charged nitrogen atom in their structure.

Curvature induced structural changes of the chicken villin headpiece subdomain by single walled carbon nanotubes.

Carbon nanotubes (CNTs) are identified as potential candidates for drug and biomolecular loading and delivery. CNTs of different chiralities have different diameters, which may significantly affect their abilities to interact with different types of biomolecules. Herein, we employ classical molecular dynamics simulation to provide insight into the curvature-dependent interactions between a model protein, chicken villin headpiece subdomain (HP36), with CNTs having chiralities (8,8), (12,12), and (20,20). It is revealed that, with increasing radii, the protein encounters more aromatic carbon atoms on the surface of the CNT, leading to its increasing strength of adsorption. However, the extent of adsorption has a limiting magnitude, after which an increase in the radius of the nanotube has practically no effect on the extent of adsorption. Spontaneous encapsulation of the protein was demonstrated using a (28,28) CNT, where the protein is found to undergo insignificant structural perturbation. Finally, steered molecular dynamics simulations have been performed to mimic the force-induced release of the protein from within the nanotube cavity. It has been identified that a minimum force of ∼300 pN and a minimum velocity of 4 Å ns-1 are required to release the protein from the CNT at 300 K. Any external force below the critical magnitude and inducing velocity less than 4 Å ns-1 allows the translocation of the protein through the inner surface of the CNT; however, before being released, the protein undergoes unfolding, thereby losing the secondary structure and biological activity.

CP-MLR/PLS directed quantitative structure-activity relationship study on the CDK8 inhibitory activity: The derivatives of naphthyridine and isoquinoline

The CDK8 and 7dF3 inhibition activity of naphthyridine and isoquinoline derivatives have been quantitatively analyzed in terms of Dragon descriptors. The statistically validated quantitative structure-activity relationship (QSAR) models provided rationales to explain the inhibition activities of these congeners. The descriptors identified through CP-MLR analysis for the CDK8 inhibitory activity have highlighted the role of sum of the topological distances between N..N (T(N..N)), distance/detour ring index of order 6 (D/Dr06), aromatic ratio (ARR), number of double bonds (nDB), number of 6-membered rings (nR06), number of sulphur atoms (nS), number of unsubstituted sp2 hybridized aromatic carbon atoms (nCaH), number of aliphatic N hydrazines (nN-N), number of aromatic primary amines (nNH2Ph) and certain atom centered fragments such as R--CH--R (C-024), X--CR..X (C-034), H attached to C1(sp3)/C0(sp2) (H-047) and RCO-N</>N-X=X (N-072) to quantify the inhibitory actions. The highest eigen value n.2 of Burden matrix/weighted by atomic polarizabilites (BEHp2) and atomic Sanderson electronegativities weighted Geary autocorrelation of lag 8 (descriptor GATS8e) have also shown prevalence to model the CDK8 inhibitory activity. PLS analysis has also corroborated the dominance of CP-MLR identified descriptors. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly. The models obtained from the descriptor pool that was chosen for the CDK8 inhibitory activity is able to explain nearly 74% variance in the observed 7dF3 activities of titled compounds.

In-Situ Photoelectron Spectroscopy Investigation of Sulfurization-Induced Sodiophilic Sites with Model Systems of α-sexithiophene and p-sexiphenyl

Uncontrollable sodium dendrite growth results in poor cycling performance and severe safety issues, hindering practical applications of sodium metal batteries (SMBs). To stabilize sodium metal anodes (SMAs), various strategies have been developed including employing anode hosts and electrolyte additives to establish protective layers. Nevertheless, the understanding of interaction mechanisms between protective materials and SMAs is still limited, which is crucial for the rational design of protective materials. In this work, we investigated the interaction mechanism between sodium metal and sulfur-containing functional groups with comparative model systems of α-sexithiophene (6T) and p-sexiphenyl (6P) through in-situ photoelectron spectroscopy investigations and density functional theory (DFT) calculations. Our results show that sodium atoms tend to interact with sulfur atoms and their connected carbon atoms simultaneously as well as the aromatic carbon atoms of the end groups of 6T molecules, while no chemical interaction between Na and 6P molecules is observed. The observed sulfurization-induced sodiophilic sites can shed light on the rational design of sulfur-containing protective materials and the relevant interface engineering to stabilize SMAs.

Molecular docking and in vitro experiments verified that kaempferol induced apoptosis and inhibited human HepG2 cell proliferation by targeting BAX, CDK1, and JUN.

Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.

Ultrasonic extraction of oil shale bitumen and study of its structural features using GC-MS and NMR techniques

ABSTRACT Oil shale is a raw material that is considered to be an alternative fossil fuels and it is widely used in producing energy and chemicals. Oil shale bitumen identification are not widely described in literature. This article tackles the structural elucidation of oil shale bitumen using gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy with a short sample preparation step, based on ultrasonic-assisted liquid extraction. The ultrasonic-assisted extraction was examined in terms of solvent type and volume, sample size, sonication time and temperatures. A bitumen recovery of 17.7 wt% dmmf (dry-mineral-matter-free) was achieved when 0.50 g of shale was mixed with 20 mL THF and sonicated for 10 min at ultrasonic power of 120 W at 45°C. GC-MS of the bitumen showed high polar oxygenated compounds with more than 20 wt% being esters and ethers. Small concentrations of thiols and amides have been also found. The structural identification of bitumen was carried out using 1H-NMR and 13C-NMR and the results showed highly aliphatic character bitumen, consisting of aromatic, paraffinic, naphthenic and olefinic hydrogen and carbon atoms. These results suggested that ultrasonic solvent extraction could be an efficient and environment-friendly method for obtaining of bitumen from oil shale.

Fine adjustments of thermo-vibrations between residues surrounding the active center in protein using dual artificial intelligence approaches and computer simulations

Adjustments of thermo-vibrations in proteins should be anticipated to provide novel helpful understanding of its properties. R111 and Q112 in the strand structure between the two domains of papain were repeatedly replaced to increase the thermo-vibration between residues surrounding its active center. This occurs due to collaborative activities composed of selections by deep neural network, verification by molecular dynamics simulations, and trainings of deep neural network by the verification results. The three replacements (R111Y-Q112K, R111C-Q112N, and R111W-Q112E) were found to increase the thermo-vibration and were expected to attain higher-temperature characteristics while at a normal temperature. The decision tree highlighted aromatic carbon and oxygen atoms in the 111th amino acid and carbon and nitrogen atoms in the 112th amino acid as influential factors. These atoms should be kept in mind to effectively carry out the collaborative activities.

Tandem Mass Spectrometric Characterization of the Molecular Radical Cations of Asphaltenes

Asphaltenes, the heaviest fraction of crude oil, are problematic for the oil industry for several reasons. For example, they have a tendency to precipitate out of oil pipelines, thus causing clogs. Further, they can foul catalysts used in refining of crude oil. However, the lack of knowledge on the exact molecular structures of asphaltenes has long prevented addressing the above problems and also hindered finding financially beneficial uses for asphaltenes. This paper focuses on recent advances on the structural characterization of the molecular radical cations of asphaltenes based on collision-activated dissociation (CAD) experiments performed using linear quadrupole ion trap mass spectrometers coupled to an Orbitrap detector. Stable molecular radical cations are readily generated from asphaltenes upon atmospheric pressure chemical ionization (APCI) when using CS2 as the solvent because this solvent cannot transfer a proton to analytes. MS2–MS5 experiments based on ion-source CAD (ISCAD), ion-trap CAD (ITCAD), and/or medium-energy CAD (MCAD) were explored for the structural characterization of these molecular radical cations by using model compounds. Energy-resolved MCAD experiments were identified as the most useful experiments because they provide substantially more structural information for the radical cations than the other CAD experiments mentioned above. In some MSn experiments, MSn–1 was first performed in the ion trap, followed by isolation of a desired ion in the ion trap and transfer into the MCAD collision cell, wherein it was subjected to energy-resolved MCAD followed by high-resolution detection of the fragment ions. The various CAD experiments were used to obtain information on compounds in asphaltene samples with different origins, such as the aliphatic carbon content, molecular weight distributions (MWDs), average molecular weight, number of aromatic carbon atoms, number of aromatic rings in the core, and relative abundances of single-core and multicore compounds.

QSAR, pharmacophore modeling and molecular docking studies to identify structural alerts for some nitrogen heterocycles as dual inhibitor of telomerase reverse transcriptase and human telomeric G-quadruplex DNA

BackgroundTelomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA are amongst the favorable target for researchers to discover novel and more effective anticancer agents. To understand and elucidate structure activity relationship and mechanism of inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA, a QSAR modeling and molecular docking were conducted.ResultsTwo robust QSAR model were obtained which consist of full set QSAR model (R2: 0.8174, CCCtr: 0.8995, Q2loo: 0.7881, Q2LMO: 0.7814) and divided set QSAR model (R2: 0.8217, CCCtr: 0.9021, Q2loo: 0.7886, Q2LMO: 0.7783, Q2-F1: 0.7078, Q2-F2: 0.6865, Q2-F3: 0.7346) for envisaging the inhibitory activity of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The analysis reveals that carbon atom exactly at 3 bonds from aromatic carbon atom, nitrogen atom exactly at six bonds from planer nitrogen atom, aromatic carbon atom within 2 A0 from the center of mass of molecule and occurrence of element hydrogen within 2 A0 from donar atom are the key pharmacophoric features important for dual inhibition of TERT and human telomeric G-quadruplex DNA. To validate this analysis, pharmacophore modeling and the molecular docking is performed. Molecular docking analysis support QSAR analysis and revealed that, dual inhibition of TERT and human telomeric DNA is mainly contributed from hydrophobic and hydrogen bonding interactions.ConclusionThe findings of molecular docking, pharmacophore modelling, and QSAR are all consistent and in strong agreement. The validated QSAR analyses can detect structural alerts, pharmacophore modelling can classify a molecule's consensus pharmacophore involving hydrophobic and acceptor regions, whereas docking analysis can reveal the mechanism of dual inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The combination of QSAR, pharmacophore modeling and molecular docking may be useful for the future drug design of dual inhibitors to combat the devastating issue of resistance.Graphical abstract

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity.

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.

DETERMINATION OF WOOD COMPOSITION USING SOLID-STATE 13C NMR SPECTROSCOPY

In recent years, solid-state 13C NMR spectroscopy using the technique of cross-polarization (CP) and sample rotation at a magic angle (MAS) has been widely used in the analysis of plant materials, including wood. Knowledge of the composition, structure and behavior of wood components under various conditions is of great importance, since the properties of wood materials depend on this. In this work, differences in the composition of wood belonging to various tree species growing in central Russia (spruce, aspen, birch, oak, linden, pine, poplar and larch) were revealed using CP MAS 13C NMR spectroscopy. The assignment of various peaks in CP MAS 13C NMR spectra to the main components of wood was carried out. It was shown that cellulose is present in its amorphous and crystalline forms, the presence of lignin was unambiguously confirmed by the signals of aromatic carbon atoms, and hemicelluloses were detected by the signals from the carbon atoms of methyl groups of acetylxylose and L-rhamnose. According to the integral intensities, the total ratio of cellulose and hemicelluloses to lignin was determined: the largest amount of lignin was found in coniferous wood (spruce, larch and pine), and the smallest amount of lignin was detected in deciduous species (aspen, oak, linden, birch and poplar).

CP MAS 13C NMR SPECTROSCOPY IN DETERMINATION OF SPECIFIC DIFFERENCES IN COMPOSITION OF WOOD

In recent years solid-state 13C NMR spectroscopy using the technique of cross-polarization (CP) and sample rotation at a magic angle (MAS) has been used in the analysis of plant materials, including wood. Knowledge of the composition, structure and behavior of wood components in different conditions is of great importance, since the properties of wood materials depend on this. In this work differences in the composition of various tree species wood in central Russia (birch, aspen, spruce, and larch) were revealed using CP MAS 13C NMR spectroscopy. Assignment of various peaks in CP MAS 13C NMR spectra with the main components of wood was carried out. It was shown that cellulose is presented in amorphous and crystalline forms, the presence of lignin is unambiguously confirmed by signals of aromatic carbon atoms, and hemicellulose is detected by signals from carbon atoms of methyl groups of acetylxylose and L-rhamnose. According to the integral intensities, the total proportion of cellulose and hemicellulose in relation to lignin was determined: the largest amount of lignin was found in coniferous wood (spruce, larch), and the smallest amount of lignin was detected in deciduous species (aspen and birch).