SUBSTITUENT EFFECT ON THE BINDING MODE AND TOXICITY OF SELECTED 1,4-BENZODIAZEPIN-2-ONE

Extended abstract: 1,4-benzodiazepin-2-ones (BZ) are effective in the treatment of depression, anxiety, epilepsy, insomnia, etc [1]. The structural modifications of 1,4-benzodiazepin-2-ones allow new areas of application due to the change in reactivity, potential binding modes, and stability. A series of eight BZs (Figure 1) has been selected to examine the effect of substituents on the binding energy towards µ-opioid receptor, Lipinski’s rules, and toxicity. Out of many available structures, the selected BZs have four positions in which the substituents were changed [2]. In position R1 an electron-withdrawing (NO2, CN) and electron-donating groups (Cl) are present [2]. The positions R2 and R3 contain H, OH, and CH3 groups. Only bromazepam, a commonly used drug, has nitrogen atom in the second aromatic ring. The structures of selected benzodiazepines were optimized in the Gaussian Program Package at the M06-2X/6-311++G(d,p) level of theory. The molecular docking studies were performed on the µ-opioid receptor (PDB: 4DKL) in AutoDOCK 4.0. The binding site of protein was determined by the presence of morphinan antagonist in the crystal structure. For the toxicity evaluation, the ProTox-II was used. All of the investigated compounds meet Lipinski’s rules of five: the molecular weight below 500 Da, the logP lower than 5, the number of H-bond donors lower than five, and H-bond acceptors lower than 10. When the toxicity is concerned, the selected BZs fall within several categories. Nordiazepam and diazepam have the lowest predicted LD50 dose of 48 mgkg-1, and they belong to the class II compounds which are fatal if swallowed. 7-cyano-1,4-benzodiazepin-2-one has lower toxicity with an LD50 value of 290 mgkg-1 (class III compounds: toxic if swallowed). The ciano group in structure is probably responsible for the hydrogen bond formation with the neighboring amino acids, as examined below. The rest of the compounds belong to the class IV: harmful if swallowed, with LC50 values ranging from 550 (nitrazepam) to 2000 (clonazepam) mgkg-1. The substituent effect on the toxicity is very complex, as all of the investigated compounds have several active positions. The values of binding energies range from -29.3 (bromazepam) to -22.8 (nordiazepam) kJmol-1. Due to the similarity in structure, all of the investigated compounds have similar values of the binding energies and in all cases, this is a favorable process. The presence of an N atom in the second ring structure is an important structural moiety as this is the only feature that differentiates bromazepam from other compounds. The importance of electronegative groups in position R1 is proven in the case of 7-cyano-1,4-benzodiazepin-2-one and nitrazepam. In general, compounds with two electronegative substituents (Cl, NO2, and OH) have higher binding energies. Further research is needed to obtain a detailed structure-activity relationship model that will correlate the substituent properties with toxicity/protein binding affinity.This work was supported by the Ministry of Science and Technological Development of the Republic of Serbia (Contract Nos. 451-03-9/2021-14/200378 and 451-03-9/2021-14/200146)Publishe

Mechanism of Antiradical Activity of Newly Synthesized 4,7-Dihydroxycoumarin Derivatives-Experimental and Kinetic DFT Study

Coumarin derivatives have proven beneficial biological activities, but the mechanism of their radical scavenging potency is not fully understood. In this study, the antiradical capacity of two newly synthesized 4,7-dihydroxycoumarin derivatives: (E)-3-(1-((3-hydroxy-4-methoxyphenyl)amino)-ethylidene)-2,4-dioxochroman-7-yl acetate (A-3OH) and (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A-4OH) towards HO center dot were examined by Electron Paramagnetic Resonance (EPR) Spectroscopy and Density Functional Theory (DFT). The compounds were fully characterized by the elemental microanalysis, IR, and NMR spectroscopies. The effect of pH on the acid-base equilibria is separately discussed and the predominant species at the physiological pH were determined. Several common mechanisms (Hydrogen Atom Transfer (HAT), Single-Electron Transfer followed by Proton Transfer (SET-PT), Sequential Proton Loss followed by Electron Transfer (SPLET), Radical Adduct Formation (RAF), and Intramolecular Hydrogen Atom Abstraction (iHAA)) of radical scavenging were investigated based on thermodynamic and kinetic parameters. EPR results indicated that both compounds significantly reduce the amount of present HO center dot. The results of the kinetic DFT study demonstrated that both compounds predominantly exhibit antiradical capacity through HAT and SPLET mechanisms. The estimated overall rate constants (k(overall)) proved that A-4OH shows better antioxidant capacity than A-3OH which is well-correlated with the results obtained by EPR measurement

ANTIOKSIDATIVNI KAPACITET ANTRAHINONA IZ BILJKE RUBIA CORDIFOLIA LINN

In this study, the antioxidant and antiradical capacities of anthraquinones from Rubia cordifolia Linn were determined using the DFT method. The thermodynamically most favorable reaction pathways of antioxidant mechanisms were defined, as well as the most favorable antiradical reaction mechanisms for the deactivation of methylperoxyl and methoxy radicals. The calculations were done in the gas phase. HAT is thermodynamically the most favorable mechanism of antioxidant action of the studied anthraquinones, while the most probable mechanism of deactivation of methylperoxyl and methoxy radicals is the SPLET mechanism.Publishe

Several coumarin derivatives and their Pd(ii) complexes as potential inhibitors of the main protease of SARS-CoV-2, anin silicoapproach

© The Royal Society of Chemistry 2020. The global pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused many fatalities among people and significantly influenced the global economy. Since efficient treatment is not available, the computational methods in biology and chemistry are a promising starting point towards adequate medication. Three previously synthesized coumarin derivatives and their Pd(ii) complexes were examined for the binding affinity towards the Mproprotein of SARS-CoV-2 by molecular docking and compared to two Food and Drug Administration (FDA) drugs,cinanserinandchloroquine. All of the investigated compounds bind to the active position of the mentioned protein. Coumarin-Pd(ii) complexes showed higher binding affinities compared to the approved drugs. The bindings of the bis(3-(1-((3-chlorophenyl)amino)ethylidene)-chroman-2,4-dione) palladium(ii) complex, its corresponding ligand, andcinanserinto SARS-CoV-2 Mprowere further subjected to the molecular dynamics simulations. The binding free energies, computed by MM/PBSA approach were analyzed in detail and the importance of specific interactions outlined. These results showed that the molecules bearing structural similarity to the approved drugs and their complexes have the potential to inhibit the functional activity of SARS-CoV-2 protease and further experimental studies should be undertaken

Chalcone derivative cytotoxicity activity against MCF-7 human breast cancer cell QSAR study

Chalcones and their derivatives possess a wide range of significant pharmacological activities; among the most important ones is their anticancer activity. For this reason we performed a Quantitative Structure-Activity Relationships (QSAR) study of their anticancer activity against MCF-7 human breast cancer cell lines. In this work, several descriptor options were tested on the dataset containing 93 molecular structures, using ERM (Enhanced Replacement Method). The best models were found using merely two dimensional descriptors. The two dimensional descriptor pool was further expanded using several nonlinear transformations, which resulted in an optimal five molecular descriptor model that showed very good predictive ability. Thus, ERM was capable of finding a simple to interpret and understand model that nonetheless addresses nonlinearities between the descriptors and the activity. Furthermore, the acquired model is very straightforward to use since it does not require the optimization of chemical structures for the calculation of three dimensional descriptors.Fil: Dusan, Dimic. University of Belgrade; SerbiaFil: Mercader, Andrew Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Universidad Nacional de la Plata; ArgentinaFil: Castro, Eduardo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Universidad Nacional de la Plata; Argentin

Personalization of Search Results Representation of a Digital Library

The process of discovering appropriate resources in digital libraries within universities is important, as it can have a big effect on whether retrieved works are useful to the requester. The improvement of the user experience with the digital library of the University of Novi Sad dissertations (PHD UNS) through the personalization of search results representation is the aim of the research presented in this paper. There are three groups of PHD UNS digital library users: users from the academic community, users outside the academic community, and librarians who are in charge of entering dissertation data. Different types of textual and visual representations were analyzed, and representations which needed to be implemented for the groups of users of PHD UNS digital library were selected. After implementing these representations and putting them into operation in April 2017, the user interface was extended with functionality that allows users to select their desired style for representing search results using an additional module for storing message logs. The stored messages represent an explicit change in the results representation by individual users. Using these message logs and ELK technology stack, we analyzed user behavior patterns depending on the type of query, type of device, and search mode. The analysis has shown that the majority of users of the PHD UNS system prefer using the textual style of representation rather than the visual. Some users have changed the style of results representation several times and it is assumed that different types of information require a different representation style. Also, it has been established that the most frequent change to the visual results representation occurs after users perform a query which shows all the dissertations from a certain time period and which is taken from the advanced search mode; however, there is no correlation between this change and the client’s device used

Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: The role of acid-base equilibria

© 2021 The Royal Society of Chemistry. The recently declared global pandemic of a new human coronavirus called SARS-CoV-2, which causes respiratory tract disease COVID-19, has reached worldwide resonance and global efforts are being made to look for possible cures. Sophisticated molecular docking software, as well as available protein sequence and structure information, offer the ability to test the inhibition of two important targets of SARS-CoV-2, furin (FUR) enzyme, and spike glycoprotein, or spike protein (SP), that are key to host cell adhesion and hijacking. The potential inhibitory effect and mechanism of action of acid-base forms of different antiviral drugs, dominant at physiological pH, chloroquine (CQ), hydroxychloroquine (HCQ), and cinanserin (CIN), which have been shown to be effective in the treatment of SARS-CoV-2 virus, is reported with the special emphasis on their relative abundances. On the other hand, the potential inhibitory effect of the dominant acid-base forms of quercetin (Q) and its oxidative metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H) benzofuranone (BZF), which are constituents of traditional food products believed to exhibit antiviral effects, was also examined. The undertaken study includes the determination of the major energy contributions to the binding energy as well as in-depth analysis of amino acid residues at the active pocket and possible interactions. The approach that we propose here may be an additional strategy for combating the deadly virus by preventing the first step of the virus replication cycle. Preliminary research has shown that the investigated compounds exert an inhibitory effect against the SARS-CoV-2 furin enzyme and spiked glycoprotein through different acid-base forms. These investigations may be helpful in creating potential therapeutic agents in the fight against the SARS-CoV-2 virus. On the other hand, the results we predicted in this computational study may be the basis for new experimental in vitro and in vivo studies. This journal i

The interaction of protonated octopamine and norepinephrine with β1-adrenergic receptor: Molecular docking and dynamical simulation

© 2020, Serbian Society of Computational Mechanics. In the current study, the interaction mechanisms between protonated neurotransmitters: octopamine (4-(2-amino-1-hydroxyethyl)phenol) and norepinephrine (4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol) with the β-1 adrenergic receptor (β1AR) were examined by molecular docking, molecular dynamics (MD) simulations and MM/PBSA free energy calculations. The investigated receptor belongs to the G-protein coupled receptor group. The investigation was carried out at physiological pH=7.4. It was estimated that both compounds exist in the protonated form in the water at physiological pH. It was found that both protonated neurotransmitters established similar interactions with amino acid residues of the receptor, such as salt bridges, conventional hydrogen bonds, π-σ, and T-shaped π-π interactions, as shown by molecular docking simulations. As the initial structures for MD simulation with a total time of 10ns the most stable docking structures were used. The presented results are expected to provide some useful information for the design of specific β1AR agonists

Structural characterization of kaempferol: A spectroscopic and computational study

© 2019 Macedonian Journal of Chemistry and Chemical Engineering. Calculations based on the density functional theory, with the B3LYP functional and the 6-311++G(d,p) basis set, were performed with the aim of confirming the molecular structure and spectro-scopic characteristics of kaempferol, a naturally occurring flavonoid molecule. The electronic structure of kaempferol was examined using NBO analysis. The assigning of the experimentally obtained IR and Ra-man spectra was performed after the best-fit-based comparison with theoretical spectra. The 13C and 1H NMR experimental spectra were related to the theoretically obtained values of the chemical shifts deter-mined by the GIAO method. The correlation coefficient and the average absolute error values proved B3LYP-D3 to be an adequate method in describing the NMR parameters of kaempferol. Molecular dock-ing analysis was carried out in order to identify the potency of inhibition of the title molecule against hu-man procalcitonin. The inhibition activity was obtained for 10 conformations of ligand inside the protein