Combined Pharmacophore Modeling, 3D-QSAR, Molecular Docking and Molecular Dynamics Study on Indolyl-aryl-sulfone Derivatives as New HIV1 Inhibitors

The present study deals with the in silico of 45 indolyl-aryl-sulfones known as anti-HIV1. The data were collected from recent previously reported inhibitors and divided into a sub-set of 33 compounds as the training set and the remaining 12 compounds were kept in the test set. The selected pharmacophore–ADRRR–yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.930, Q2 = 0.848, and RMSE = 0.460). The predictive power of the established pharmacophore model was validated with an external test (r2 = 0.848). A systematic virtual screening workflow shows an enrichment factor and has revealed a high predictive power. Then the model was used to screen the filtered PubChem database mapping all chemical features of model pharmacophore. The recognized hits were further assessed by in silico ADMET studies. Molecular dynamics also used to explore the stability of obtained complexes. Finally, these selected compounds are probably to become a good lead molecule for the development of effective anti-HIV-1 drugs

Antibacterial and antibiofilm activity of Abroma augusta stabilized silver (Ag) nanoparticles against drug-resistant clinical pathogens

Infectious diseases remain among the most pressing concerns for human health. This issue has grown even more complex with the emergence of multidrug-resistant (MDR) bacteria. To address bacterial infections, nanoparticles have emerged as a promising avenue, offering the potential to target bacteria at multiple levels and effectively eliminate them. In this study, silver nanoparticles (AA-AgNPs) were synthesized using the leaf extract of a medicinal plant, Abroma augusta. The synthesis method is straightforward, safe, cost-effective, and environment friendly, utilizing the leaf extract of this Ayurvedic herb. The UV-vis absorbance peak at 424 nm indicated the formation of AA-AgNPs, with the involvement of numerous functional groups in the synthesis and stabilization of the particles. AA-AgNPs exhibited robust antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). The MIC values of AA-AgNPs ranged from 8 to 32 μg/mL. Electron microscopic examination of the interaction of AA-AgNPs with the test bacterial pathogens showed a deleterious impact on bacterial morphology, resulting from membrane rupture and leakage of intracellular components. AA-AgNPs also demonstrated a dose-dependent effect in curtailing biofilm formation below inhibitory doses. Overall, this study highlights the potential of AA-AgNPs in the successful inhibition of both the growth and biofilms of MRSA and VRE bacteria. Following studies on toxicity and dose optimization, such AgNPs could be developed into effective medical remedies against infections

Identification of a novel Sorcin isoform with a different C-terminal but intact dimerization property

Abstract Sorcin (Sri), a member of penta EF-hand protein family plays a diverse role in maintaining calcium homeostasis, cell cycle and vesicular trafficking. Sri is highly conserved amongst mammals and consists of N-terminal glycine rich domain and C-terminal calcium binding domain that mediates its dimerization and interacts with different compounds. In the present study, with the help of combination of computational and molecular biology techniques, we have identified a novel isoform (Sri-N) in mouse which differs only in the C-terminal domain with that of Sri reported earlier. The novel isoform contains a new last exon that is different from the one present in the reported transcript (Sri). The presence of the novel isoform was further validated in different tissues by RT-PCR and DNA sequencing. The transcript was conceptually translated and subjected to in-silico analysis using different bioinformatics tools. The novel transcript variant encodes for a longer protein isoform without any change in the sub-cellular localization as predicted by PSORT-II online tool. Molecular modelling was performed to compare the structural changes in Sri-N and Sri isoforms. The structural characterization of the novel isoform using MD simulation depicted its overall stability under the physiological conditions. The molecular docking of proteins with various chemotherapeutic drugs revealed that their binding affinity is more for Sri-N as compared to that for the previously reported transcript Sri

In-Silico Analysis of Phytocompounds of <i>Olea europaea</i> as Potential Anti-Cancer Agents to Target PKM2 Protein

Globally, cancer is the second leading cause of mortality and morbidity. The growth and development of cancer are extremely complex. It is caused by a variety of pathways and involves various types of enzymes. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, that catalyses the last steps of glycolysis to produce energy. PKM2 is relatively more expressed in tumour cells where it tends to exist in a dimer form. Various medicinal plants are available that contain a variety of micronutrients to combat against different cancers. The phytocompounds of the olive tree (Olea europaea) leaves play an important role in inhibiting the proliferation of several cancers. In this study, the phytocompounds of olive leaf extract (OLE) were studied using various in silico tools, such as pkCSM software to predict ADMET properties and PASS Online software to predict anticancer activity. However, the molecular docking study provided the binding energies and inhibition constant and confirmed the interaction between PKM2 and the ligands. The dynamic behaviour, conformational changes, and stability between PKM2 and the top three hit compounds (Verbascoside (Ver), Rutin (Rut), and Luteolin_7_O_glucoside (Lut)) are studied by MD simulations

Fabrication of Zinc Oxide-Xanthan Gum Nanocomposite via Green Route: Attenuation of Quorum Sensing Regulated Virulence Functions and Mitigation of Biofilm in Gram-Negative Bacterial Pathogens

The unabated abuse of antibiotics has created a selection pressure that has resulted in the development of antimicrobial resistance (AMR) among pathogenic bacteria. AMR has become a global health concern in recent times and is responsible for a high number of mortalities occurring across the globe. Owing to the slow development of antibiotics, new chemotherapeutic antimicrobials with a novel mode of action is required urgently. Therefore, in the current investigation, we green synthesized a nanocomposite comprising zinc oxide nanoparticles functionalized with extracellular polysaccharide xanthan gum (ZnO@XG). Synthesized nanomaterial was characterized by structurally and morphologically using UV-visible spectroscopy, XRD, FTIR, BET, SEM and TEM. Subinhibitory concentrations of ZnO@XG were used to determine quorum sensing inhibitory activity against Gram-negative pathogens, Chromobacterium violaceum, and Serratia marcescens. ZnO@XG reduced quorum sensing (QS) regulated virulence factors such as violacein (61%), chitinase (70%) in C. violaceum and prodigiosin (71%) and protease (72%) in S. marcescens at 128 &micro;g/mL concentration. Significant (p &le; 0.05) inhibition of biofilm formation as well as preformed mature biofilms was also recorded along with the impaired production of EPS, swarming motility and cell surface hydrophobicity in both the test pathogens. The findings of this study clearly highlight the potency of ZnO@XG against the QS controlled virulence factors of drug-resistant pathogens that may be developed as effective inhibitors of QS and biofilms to mitigate the threat of multidrug resistance (MDR). ZnO@XG may be used alone or in combination with antimicrobial drugs against MDR bacterial pathogens. Further, it can be utilized in the food industry to counter the menace of contamination and spoilage caused by the formation of biofilms

Identification of potent inhibitors of NEK7 protein using a comprehensive computational approach

NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) softwares were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein-ligand complexes with docking scores of - 29.66 kJ/mol and - 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein-ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.Funding Agencies|Princess Nourah bint Abdulrahman University, Riyadh, Saudi ArabiaPrincess Nourah bint Abdulrahman University [PNURSP2022R12]</p

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 &amp; AKRB10) : Potential Lead Molecules for Treatment of Colon Cancer

Both members of the aldo-keto reductases (AKRs) family, AKR1B1 and AKR1B10, are over-expressed in various type of cancer, making them potential targets for inflammation-mediated cancers such as colon, lung, breast, and prostate cancers. This is the first comprehensive study which focused on the identification of phenylcarbamoylazinane-1, 2,4-triazole amides (7a-o) as the inhibitors of aldo-keto reductases (AKR1B1, AKR1B10) via detailed computational analysis. Firstly, the stability and reactivity of compounds were determined by using the Guassian09 programme in which the density functional theory (DFT) calculations were performed by using the B3LYP/SVP level. Among all the derivatives, the 7d, 7e, 7f, 7h, 7j, 7k, and 7m were found chemically reactive. Then the binding interactions of the optimized compounds within the active pocket of the selected targets were carried out by using molecular docking software: AutoDock tools and Molecular operation environment (MOE) software, and during analysis, the Autodock (academic software) results were found to be reproducible, suggesting this software is best over the MOE (commercial software). The results were found in correlation with the DFT results, suggesting 7d as the best inhibitor of AKR1B1 with the energy value of -49.40 kJ/mol and 7f as the best inhibitor of AKR1B10 with the energy value of -52.84 kJ/mol. The other potent compounds also showed comparable binding energies. The best inhibitors of both targets were validated by the molecular dynamics simulation studies where the root mean square value of &amp;lt;2 along with the other physicochemical properties, hydrogen bond interactions, and binding energies were observed. Furthermore, the anticancer potential of the potent compounds was confirmed by cell viability (MTT) assay. The studied compounds fall into the category of drug-like properties and also supported by physicochemical and pharmacological ADMET properties. It can be suggested that the further synthesis of derivatives of 7d and 7f may lead to the potential drug-like molecules for the treatment of colon cancer associated with the aberrant expression of either AKR1B1 or AKR1B10 and other associated malignancies.Funding Agencies|Princess Nourah bint Abdulrahman University [PNURSP2022R12]</p

Biosynthesized Zinc Oxide Nanoparticles Disrupt Established Biofilms of Pathogenic Bacteria

Global emergence and persistence of the multidrug-resistant microbes have created a new problem for management of diseases associated with infections. The development of antimicrobial resistance is mainly due to the sub-judicious and unprescribed used of antimicrobials both in healthcare and the environment. Biofilms are important due to their role in microbial infections and hence are considered a novel target in discovery of new antibacterial or antibiofilm agents. In this article, zinc oxide nanoparticles (ZnO-NPs) were prepared using extract of Plumbago zeylanica. ZnO-NPs were characterized and then their antibiofilm activity was tested against Gram-positive and Gram-negative bacteria. The ZnO-NPs were polydispersed, and the average size was obtained as 24.62 nm. The presence of many functional groups indicated that phytocompounds of P. zeylanica were responsible for the synthesis, capping, and stabilization of ZnO-NPs. Synthesized NPs inhibited the biofilm formation of E. coli, S. aureus, and P. aeruginosa by 62.80%, 71.57%, and 77.69%, respectively. Likewise, concentration-dependent inhibition of the EPS production was recorded in all test bacteria. Microscopic examination of the biofilms revealed that ZnO-NPs reduced the bacterial colonization on solid support and altered the architecture of the biofilms. ZnO-NPs also remarkably eradicated the preformed biofilms of the test bacteria up to 52.69%, 59.79%, and 67.22% recorded for E. coli, S. aureus, P. aeruginosa, respectively. The findings reveal the ability of green synthesized zinc oxide nanoparticles to inhibit, as well as eradicate, the biofilms of Gram-positive and Gram-negative bacteria

Multi-spectroscopic and molecular modelling approach to investigate the interaction of riboflavin with human serum albumin

<p>Riboflavin (RF) plays an important role in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Human serum albumin (HSA) is an important protein involved in the transportation of drugs, hormones, fatty acid and other molecules which determine the biodistribution and physiological fate of these molecules. In this study, we have investigated the interaction of riboflavin RF with HSA under simulative physiological conditions using various biophysical, calorimetric and molecular docking techniques. Results demonstrate the formation of riboflavin–HSA complex with binding constant in the order of 10⁴ M⁻¹. Fluorescence spectroscopy confirms intermediate strength having a static mode of quenching with stoichiometry of 1:1. Experimental results suggest that the binding site of riboflavin mainly resides in sub-domain IIA of HSA and that ligand interaction increases the <i>α</i>-helical content of HSA. These parameters were further verified by isothermal titration calorimetry ITC which confirms the thermodynamic parameters obtained by fluorescence spectroscopy. Molecular docking was employed to suggest a binding model. Based on thermodynamic, spectroscopic and computational observations it can be concluded that HSA-riboflavin complex is mainly stabilized by various non-covalent forces with binding energy of −7.2 kcal mol⁻¹.</p

Biosynthesized Zinc Oxide Nanoparticles Disrupt Established Biofilms of Pathogenic Bacteria

Global emergence and persistence of the multidrug-resistant microbes have created a new problem for management of diseases associated with infections. The development of antimicrobial resistance is mainly due to the sub-judicious and unprescribed used of antimicrobials both in healthcare and the environment. Biofilms are important due to their role in microbial infections and hence are considered a novel target in discovery of new antibacterial or antibiofilm agents. In this article, zinc oxide nanoparticles (ZnO-NPs) were prepared using extract of Plumbago zeylanica. ZnO-NPs were characterized and then their antibiofilm activity was tested against Gram-positive and Gram-negative bacteria. The ZnO-NPs were polydispersed, and the average size was obtained as 24.62 nm. The presence of many functional groups indicated that phytocompounds of P. zeylanica were responsible for the synthesis, capping, and stabilization of ZnO-NPs. Synthesized NPs inhibited the biofilm formation of E. coli, S. aureus, and P. aeruginosa by 62.80%, 71.57%, and 77.69%, respectively. Likewise, concentration-dependent inhibition of the EPS production was recorded in all test bacteria. Microscopic examination of the biofilms revealed that ZnO-NPs reduced the bacterial colonization on solid support and altered the architecture of the biofilms. ZnO-NPs also remarkably eradicated the preformed biofilms of the test bacteria up to 52.69%, 59.79%, and 67.22% recorded for E. coli, S. aureus, P. aeruginosa, respectively. The findings reveal the ability of green synthesized zinc oxide nanoparticles to inhibit, as well as eradicate, the biofilms of Gram-positive and Gram-negative bacteria