Identification of selective Lyn inhibitors from the chemical databases through integrated molecular modelling approaches

In the current study, the Asinex and ChEBI databases were virtually screened for the identification of potential Lyn protein inhibitors. Therefore, a multi-steps molecular docking study was carried out using the VSW utility tool embedded in Maestro user interface of the Schrödinger suite. On initial screening, molecules having a higher XP-docking score and binding free energy compared to Staurosporin were considered for further assessment. Based on in silico pharmacokinetic analysis and a common-feature pharmacophore mapping model developed from the Staurosporin, four molecules were proposed as promising Lyn inhibitors. The binding interactions of all proposed Lyn inhibitors revealed strong ligand efficiency in terms of energy score obtained in molecular modelling analyses. Furthermore, the dynamic behaviour of each molecule in association with the Lyn protein-bound state was assessed through an all-atoms molecular dynamics (MD) simulation study. MD simulation analyses were confirmed with notable intermolecular interactions and consistent stability for the Lyn protein-ligand complexes throughout the simulation. High negative binding free energy of identified four compounds calculated through MM-PBSA approach demonstrated a strong binding affinity towards the Lyn protein. Hence, the proposed compounds might be taken forward as potential next-generation Lyn kinase inhibitors for managing numerous Lyn associated diseases or health complications after experimental validation.The Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia through the Fast-track Research Funding Program.https://www.tandfonline.com/loi/gsar20hj2022Chemical Patholog

Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors

Abstract: Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition. Graphic abstract: [Figure not available: see fulltext.

Solvent-Free Mechanochemical Synthesis of High Transition Biphenyltetracarboxydiimide Liquid Crystals

A series of high temperature alkyl and alkoxy biphenyltetracarboxydiimide liquid crystals have been prepared under ball mill method using solvent-free mechanochemical approach. The thermal properties of the prepared compounds were investigated by deferential scanning calorimetry (DSC) measurements and the textures were identified by polarized optical microscope (POM). The compounds showed smectic mesomorphic behaviour. The results showed the increasing nature of transition temperature Cr-SmC with chain length with increments of the SmC mesophase range. However, the mesophase range of the SmA was decreased with the terminal chain length either for the alkyl or alkoxy terminal groups. Moreover, the DFT theoretical calculations have been conducted give a detailed projection of the structure of the prepared compounds. A conformational investigation of the biphenyl part has been studied. A deep illustration of the experimental mesomorphic behaviour has been discussed in terms of the calculated aspect ratio. A projection of the frontier molecular orbitals as well as molecular electrostatic potential has been studied to show the effect of the polarity of the terminal chains on the level and the gab of the FMOs and the distribution of electrostatic charges on the prepared molecules

Inhibition survey with phenolic compounds against the δ- and η-class carbonic anhydrases from the marine diatom thalassiosira weissflogii and protozoan Plasmodium falciparum

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81–65.4 µM) and PfCA (KIs 0.62–78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria

Phosphonamidates are the first phosphorus-based zinc binding motif to show inhibition of β-class carbonic anhydrases from bacteria, fungi, and protozoa

A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against β-class CAs, herein we report an inhibition study with this class of compounds against β-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for β-class over human isozymes, making them interesting leads for the development of new anti-infectives

Adsorption Potential of Schizophyllum commune White Rot Fungus for Degradation of Reactive Dye and Condition Optimization: A Thermodynamic and Kinetic Study

The pollution due to dyes from textile sector is one of the major issues faced worldwide. This study was focused on the removal of the reactive dye, Drimaren Turquoise CL-B using Schizophyllum commune, a white rot fungus (WRF) keeping in mind the current environmental conditions. Different parameters like pH, sources of carbon & nitrogen, temperature, concentration of dye and C/N ratio were used to investigate their effect on the process. Maximum dye removal of 95.45% was obtained at pH 4.5, temperature 35°C, inoculum size 3 mL, veratryl alcohol (mediator), glucose (carbon source) and ammonium nitrate (nitrogen source). The enzyme activity was determined by employing enzyme assay. Laccase and Lignin peroxidase (LiP) activity was low while Manganese peroxidase (MnP) activity was highest. Maximum bio-sorption was achieved at pH 1 and 313 K. The pseudo-2nd-order kinetic model & Freundlich isotherm was best suited for the process of removal of dye. From these data, it is concluded that white rot fungus could possibly be the excellent biomaterial for elimination of synthetic dyes from wastewater

Cellulosic biomass biocomposites with polyaniline, polypyrrole and sodium alginate: Insecticide adsorption-desorption, equilibrium and kinetics studies

This work was designed to synthesize and characterize biocomposites for the adsorptive elimination of insecticide (nitenpyram). Different biocomposites were synthesized of polyaniline (PAN-PH), polypyrrole (PPY-PH) and sodium alginate (Na-Al-PH) with cellulosic biomass of peanut husk (PH), which was characterized fourier-transform infrared spectroscopy (FTIR), pHpzc and scanning electron microscope (SEM). In batch mode, different variables, i.e., contact time, pH, temperature, NP (nitenpyram) concentration and adsorbent dose effects were investigated. The adsorption capacities of PH, PAN-PH, PPY-PH and Na-Al-PH were recorded to be 13.0, 14.43, 13.61 and 11.91 (mg/g), respectively at 30 °C, 60 min contact time, 0.05 g and 2.0 pH. Pseudo second order kinetic and Freundlich isotherm models best explained the NP adsorption data. An exothermic adsorption nature of NP adsorption was observed on to PH, PAN-PH, PPY-PH and Na-Al-PH. The NP desorption was efficient with NaOH and biocomposites are competent for the adsorptive removal of NP, which can utilized for NP remediation in effluents

Benzothiazole derivatives as anticancer agents

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours

Removal of Cr(III) from Aqueous Solution Using Labeo rohita Chitosan-Based Composite

This study focusses on the synthesis of chitosan-cellulose composite membrane derived from Labeo rohita fish scales (FS) for the removal of Cr(III) from aqueous solution, while chromium is a serious threat to groundwater. Waste FS are valorized to chitosan by demineralization, deproteination, and deacetylation successively. Cellulose was extracted from sugarcane bagasse using acidic hydrolysis. Chitosan-based cellulose composite porous membrane was fabricated by evaporating solvent from polymer solution in petri dish. The impact of pH, contact time, and absorbent dosage on the removal of Cr(III) from an aqueous solution was investigated. Atomic absorption spectrophotometer was used to check the Cr(III). Results showed that chitosan comprising 85% degree of deacetylation was achieved by alkali treatment, while yield was 22%. FTIR analysis confirmed the chitosan and chitosan-cellulose-based composite membrane. Morphology studies showed that the cellulose was strongly staggered and due to the chitosan, the surface of cellulose became rougher, which is good to enhance the adsorption capacity. The maximum removal 57% of Cr(III) from aqueous solution was observed at pH 6 at 60 min and 50 mg dosage of adsorbent. The minimum removal (47%) of Cr (III) was found at pH 2. These results confer that Labeo rohita-based chitosan-cellulose composite membrane has great potential for the removal of metals from industrial effluents