Selection of antileishmanial sesquiterpene lactones from SistematX database using a combined ligand-/structure-based virtual screening approach

Molecular Diversity - Leishmaniasis refers to a complex of diseases, caused by the intracellular parasitic protozoans belonging to the genus Leishmania. Among the three types of disease...     

Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure–activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure– activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc ‘clean drug-like’ database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.     

Repurposing the antibacterial drugs for inhibition of SARS-CoV2-PLpro using molecular docking,MD simulation and binding energy calculation

Molecular Diversity - Papain-like protease (nsp-3; non-structural protein) of novel corona virus is an ideal target for developing drugs as it plays multiple important functions for viral growth...     

Discovery of inhibitors targeting protein tyrosine phosphatase 1B using a combined virtual screening approach

Molecular Diversity - Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and...     

Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach

Molecular Diversity - The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the...     

Identification of dual Acetyl-CoA carboxylases 1 and 2 inhibitors by pharmacophore based virtual screening and molecular docking approach

Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme that plays a vital role in obesity-induced type 2 diabetes and fatty acid metabolism. To identify dual inhibitors of Acetyl-CoA carboxylase1 and Acetyl-CoA carboxylase2, a pharmacophore modelling approach has been employed. The best HypoGen pharmacophore model for ACC2 inhibitors (Hypo1_ACC2) consists of one hydrogen bond acceptor, one hydrophobic aliphatic and one hydrophobic aromatic feature, whereas the best pharmacophore (Hypo1_ACC1) for ACC1 consists of one additional hydrogen-bond donor (HBD) features. The best pharmacophore hypotheses were validated by various methods such as test set, decoy set and Cat-Scramble methodology. The validated pharmacophore models were used to screen several small-molecule databases, including Specs, NCI, ChemDiv and Natural product databases to identify the potential dual ACC inhibitors. The virtual hits were then subjected to several filters such as estimated $\text{ IC}_{50}$ value, quantitative estimation of drug-likeness and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as potential starting points for the design of novel dual ACC inhibitors.     

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening,molecular docking,ADMET analysis and MD simulations

Molecular Diversity - In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has...     

Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach

JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 ( $Q_{\mathrm{test}}^{2} 0.663, R^{2}_{\mathrm{train}} 0.849$ , F value 219.3) for JAK2 and ADDRR.142 ( $Q^{2}_{\mathrm{test}}0.655, R_{\mathrm{train}}^{2}$ 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.     

Structure-based virtual screening,in silico docking,ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M^pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M^pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M^pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M^pro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M^pro target.

     

Discovery of small molecular inhibitors for interleukin-33/ST2 protein–protein interaction: a virtual screening,molecular dynamics simulations and binding free energy calculations

The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein–protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, the exploration of small molecular inhibitors is highly sought-after because of its advantages in terms of oral bioavailability and manufacturing cost. The aim of this study was to discover ST2 receptor inhibitors based on its PPIs with IL-33 in crystal structure (PDB ID: 4KC3) using virtual screening tools with pharmacophore modeling and molecular docking. From an enormous chemical space ZINC, a potential series of compounds has been discovered with stronger binding affinities than the control compound from a previous study. Among them, four compounds strongly interacted with the key residues of the receptor and had a binding free energy?<????20 kcal/mol. By intensive calculations using data from molecular dynamics simulations, ZINC59514725 was identified as the most potential candidate for ST2 receptor inhibitor in this study.

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Improved electrochemical properties of Sr2+-doped LiNi0.8Co0.2O2 synthesized via a sol-gel route using tartaric acid as a chelating agent

Single-phase undoped LiNi_0.8Co_0.2O₂ and Sr²⁺-doped LiNi_0.8Co_0.2O₂ were synthesized by a low temperature tartaric acid assisted sol-gel method. Small quantities of Sr²⁺ were used as dopants in order to improve the electrochemical characteristics, especially the capacity and cycling performance of LiNi_0.8Co_0.2O₂. The electrochemical performance of the undoped material was promising with a first discharge capacity of 174 mAh/g and 165 mAh/g after 10 cycles with a 100% cycling efficiency in the tenth cycle. Addition of Sr²⁺ for Li in minimum quantities with the Sr²⁺/Li⁺ dopant mole ratio ranging from 10⁻⁴ to 10⁻⁸ resulted in improved electrochemical properties for dopant mole ratio of 10⁻⁶. The first discharge capacity was 182 mAh/g and the tenth was 174 mAh/g at the 10th discharge. The synthesis of Sr²⁺-doped LiNi_0.8Co_0.2O₂ and its improved electrochemical properties have been discussed for the first time. The improved electrochemical properties of Sr²⁺-doped LiNi_0.8Co_0.2O₂ system are explained based on defect models.     

Improving the thermoelectric properties of thick Sb2Te3 film via Cu doping and annealing deposited by DC magnetron sputtering using a mosaic target

Thick Cu-doped Sb₂Te₃ films were deposited on flexible substrate by DC magnetron sputtering from a mosaic Cu–Sb₂Te₃ target. The Cu-doped Sb₂Te₃ films were vacuum annealed to improve their thermoelectric properties. Density functional theory was used to clarify the internal mechanism of the Cu doped into the Sb₂Te₃ system. The results showed that Cu substitution on a Sb site induced electronic states or impurity peaks of Sb₂Te₃ at a valence band maximum. The carrier concentration of the Cu-doped Sb₂Te₃ films increased as the Cu-doped concentration increased. However, the crystallite size and Seebeck coefficient of the Cu-doped Sb₂Te₃ films decreased as the Cu-doped concentration increased. Post-annealing treatment improved the microstructure and thermoelectric properties of the Cu-doped Sb₂Te₃ films. The maximum electrical conductivity and power factor values of 754.20 S/cm at 50 °C and 1.56 10⁻³ W/mK² at 100 °C were obtained in the annealed film with a Cu-doped concentration of 3 at%.     

Measurement of astrophysical S factors and electron screening potentials for d(d, n)3He reaction In ZrD2, TiD2, D2O, and CD2 targets in the ultralow energy region using plasma accelerators

The paper is devoted to study electron screening effect influence on the rate of d(d, n)³He reaction in the ultralow deuteron collision energy range in the deuterated polyethylene (CD₂), frozen heavy water (D₂O) and deuterated metals (ZrD₂ and TiD₂). The ZrD₂ and TiD₂ targets were fabricated via magnetron sputtering of titanium and zirconium in gas (deuterium) environment. The experiments have been carried out using high-current plasma pulsed accelerator with forming of inverse Z pinch (HCEIRAS, Russia) and pulsed Hall plasma accelerator (NPI at TPU, Russia). The detection of neutrons with energy of 2.5MeV from dd reaction was done with plastic scintillation spectrometers. As a result of the experiments the energy dependences of astrophysical S factor for the dd reaction in the deuteron collision energy range of 2?C7 keV and the values of the electron screening potential U _e of interacting deuterons have been measured for the indicated above target: U _e (CD₂) ? 40 eV; U _e (D₂O) ? 26 eV; U _e (ZrD₂) = 157 ± 43 eV; U _e (TiD₂) = 125±34 eV. The value of astrophysical S factor, corresponding to the deuteron collision energy equal to zero, in the experiments with D₂O target is found: S _b (0) = 58.6 ± 3.6 keV b. The paper compares our results with other available published experimental and calculated data.     

In-situ preparation of 1D CuO nanostructures using Cu2(OH)2CO3 nanoribbons as precursor for sacrifice-template via heat-treatment

One-dimensional (1D) CuO nanostructures with nanoribbons, scroll-like structure, arrays of CuO nanoparticles and nanorod-like morphologies respectively, have been successfully prepared using the single-crystalline Cu₂(OH)₂CO₃ nanoribbons as precursors for sacrifice-template via heat-treatments. The series of morphologies images for decomposition kinetics process of Cu₂(OH)₂CO₃ nanoribbons as heat-treatment temperature increased are presented in this work. The result demonstrates that the morphologies of the 1D CuO nanostructures obtained are mainly due to the ribbon-like shape of the precursors. The morphologies of CuO nanostructures also strongly depend on the heat-treatment conditions. At relatively low heat-treatment temperature and heating rate, the morphological features of the precursor can be preserved well, while arrays of CuO nanoparticles can be obtained at higher heating rate and CuO rod-like shape can be prepared with increasing heat-treatment temperature.     

Solvent-free synthesis of new spiropyrroloindole compounds using Fe3O4/TiO2/MWCNTs MNCs via multicomponent reactions: assessment of new spiropyrroloindole antioxidant activity

In this study, water extract of Spinacia oleracea leaves was used for the synthesis of Fe₃O₄/TiO₂/MWCNTs magnetic nanocomposites and high performance of this catalyst was confirmed by employing it in the solvent-free multicomponent reactions of anilines, oxalyl chloride, diamines or hydroxyamines, electron-deficient acetylenic ester, α-haloketones and Et₃N at room temperature for the generation of new spiropyrroloindoles in high yields. This catalyst could be utilized several times and has a significant role in the yield of product. The synthesized spiropyrroloindoles have NH and OH group in their structure and for this reason have good antioxidant activity. Also, by employing Gram-positive and Gram-negative bacteria and the disk diffusion procedure confirmed the antimicrobial effect of some spiropyrroloindole derivatives. The results showed that synthesized spiropyrroloindoles prevented the bacterial growth. This used process for preparation of new spiropyrroloindoles has some improvements such as low reaction time, product with high yields, and simple separation of catalyst and products.

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Selective and sensitive determination of dopamine via suppressing ascorbic acid using an N-(1-H-indole-3yl) methylene thiazole-2-amine thin film-modified glassy carbon electrode

The selective determination of dopamine (DA) was performed using a glassy carbon (GC) electrode modified with N-(1-H-indole-3yl) methylene thiazole-2-amine (IMT2A). IMT2A was deposited on the GC electrode by cyclic voltammetry. This modified electrode demonstrated an electrocatalytic effect on the oxidation of DA in the presence of uric acid (UA) and ascorbic acid (AA) using differential pulse voltammetry (DPV) method in 0.1 M phosphate buffer solution (PBS) of pH 7. Selective determination was realized in elimination of AA response on the IMT2A-modified electrode. The oxidation peak currents increased linearly with two concentration intervals of DA at pH 7 phosphate buffer. One of them is 0.25–9.15 μM, and the other is 9.15–95.1 μM. The limit of detection (LOD) was found as 0.086 μM. The proposed electrode was applied to the determination of DA in pharmaceutical preparations and human urine sample with satisfactory results.