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Myrtus communis L, is an edible medicinal plant with fruit berries used to manufacture liquors, aromatise wine, and sweet foods, beside several folk-medicinal uses. The plant is also endemic to Libya, holds promise for its medicinal properties, including anti-inflammatory, antioxidant, wound healing, and appetising effects. This work aims to explore the phytoconstituents present in the seeds and fruit peels of Myrtus communis L by GC-MS and LC-ESI-MS analysis, respectively. The work also demonstrated the in vitro and in silico antioxidant and anti-tyrosinase activities of the plant extracts. GC-MS analysis indicated the presence of 11 fatty acids in the myrtle seeds representing 78.61% of the total seeds' fatty acid contents, where the unsaturated linolenic acid (C18:3) was the major fatty acid (23.11%). Moreover, seven anthocyanins were identified by the LC-ESI-MS analysis in the fruit peels with relative percentage of 59.84% related to the total peaks area in the positive ion mode chromatogram. Among the identified compounds, petunidin 3-O-glucoside and Malvidin 3-O-rutinoside were the most abundant anthocyanins at the relative percentage of 12.48% and11.87%, respectively. Antioxidant assay showed that the ethanolic extract of the Myrtus fruit peels exhibited higher DPPH-free radical scavenging activities compared to the chloroform extract of the seeds (6.89 ± 0.12 and 2.65 ± 0.03, respectively). Similarly, the fruit peels extract was induced higher ferric reducing antioxidant power (FRAP) compared to the seeds extract (4.87 ± 1.02 and 2.10 ± 0.9, respectively. The fruit peels ethanolic extract was exhibited greatest inhibitory effect against tyrosinase enzyme with IC50 126.35 ± 0.92 compared to the activity of seeds extract at the IC50 135.27 ± 1.23. The tested extracts displayed lower level of tyrosinase inhibition activity compared to the standard arbutin (IC50 76.9 ± 0.0). The results of molecular docking simulations suggest that anthocyanins, particularly Cyanidin-3-O-rutinoside, exhibit significant binding affinity to the tyrosinase enzyme and could potentially serve as effective natural inhibitors. These compounds may interfere with the enzyme's catalytic activity by interacting with key residues in the active site. [ABSTRACT FROM AUTHOR]

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We synthesised a novel series of FGFR1 inhibitors bearing quinoline, quinoxalin and isoquinoline using a synthetic strategy employing a one pot reaction, yielding 2-hydroxy-1H-indene-1,3(2H)-dione. Structural elucidation via IR, NMR and HRMS analyses is complemented by a proposed mechanistic pathway. All newly-synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR-1. The most potent derivatives were 9a, 9b, 9c and 7b with IC50 = 5.7, 3.3, 4.1 and 3.1 μM, respectively, supported by molecular docking studies which probed the binding interactions of these compounds within the active site of the kinase. [ABSTRACT FROM AUTHOR]

The P2Y12 receptor is an important member of the purinergic receptor family, known for its critical role in platelet activation and thrombosis. In our previously published study, the acridinone analogue NSC618159 was identified as a potent antagonist of P2Y12. In this work, we investigate the conformational changes in P2Y12 when bound to NSC618159 using molecular dynamics simulations on the receptor's active and inactive forms (4PXZ and 4NTJ, respectively). It was observed that it took the systems about 7 ns and 12 ns to stabilise when NSC618159 was in complex with the active and inactive forms of P2Y12, respectively. Additionally, the binding pocket of the crystal structure 4PXZ expanded from 172.34 Å3 to an average of 661.55 Å3 when bound to NSC618159, with a maximum pocket volume of 820.49 Å3. This expansion was attributed to the pulled away transmembrane (TM) helices and the adoption of a more open conformation by extracellular loop 2 (EL2). In contrast, 4NTJ's pocket volume was mostly consistent and had an average of 1203.82 Å3. Moreover, the RMSF profile of the NSC618159-4PXZ complex showed that residues of TM-I and TM-VII had similar fluctuations to the 4NTJ crystal structure, representing the inactive form of P2Y12. Finally, the energy components and binding affinities of NSC618159 towards the active and inactive forms of P2Y12 were predicted using the MM-PBSA approach. According to the results, the binding affinity of NSC618159 towards both active (4PXZ) and inactive (4NTJ) forms of P2Y12 was found to be almost identical, with values of −43.52 and −41.68 kcal/mol, respectively. In conclusion, our findings provide new insights into the conformational changes of P2Y12 upon binding to NSC618159 and may have implications for the development of new P2Y12 antagonists with enhanced potency and specificity. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are spherical particles with a number of specific and unique physical (such as surface plasmon resonance, high electrical conductivity and thermal stability) as well as chemical (including antimicrobial activity, catalytic efficiency and the ability to form conjugates with biomolecules) properties. These properties allow AgNPs to exhibit desired interactions with the biological system and make them prospective candidates for use in antibacterial and anticancer activities. AgNPs have a quenching capacity, which produces reactive oxygen species and disrupts cellular processes (such as reducing the function of the mitochondria, damaging the cell membrane, inhibiting DNA replication and altering protein synthesis). In addition, sponge extracts contain biologically active substances with therapeutic effects. Therefore, the concurrent use of these agents may present a potential for the development of novel antitumor and antimicrobial drugs. The present study investigated the cytotoxic effects of AgNPs combined with the extracts from sponge species, Stylissa carteri or Amphimedon chloros, against various cancer cell lines and pathogenic bacterial strains. The present study was novel as it provided a further understanding of the cytotoxicity and underlying mechanisms of AgNPs. Alterations in the properties, such as size, charge and polydispersity index, of the AgNPs were demonstrated after lyophilization. Scanning electron microscopy revealed submicron-sized particles. The cytotoxic potential of AgNPs across various cancer cell lines such as lung, colorectal, breast and pancreatic cancer cell lines, was demonstrated, especially when the AgNPs were combined with sponge extracts, which suggested a synergistic effect. Analysis using liquid chromatography-mass spectrometry revealed key chemical components in the extracts, and molecular docking simulations indicated potential inhibition interactions between a number of the extract components and the epidermal growth factor receptor and tyrosine kinase receptor A. Synergistic antibacterial effects against several bacterial species such as Staphylococcus xylosus, Klebsiella oxytoca, Enterobacter aerogenes, Micrococcus spp. and Escherichia coli, were observed when AgNPs were combined with sponge ethyl acetate extracts. The results of the present study suggested a potential therapeutic application of marine-derived compounds and nanotechnology in combating cancer and bacterial infections. Future research should further elucidate the mechanistic pathways and investigate the in vivo therapeutic efficacy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 is a recently discovered member of coronaviruses (CoVs) family that is very contagious and has a high infectivity rate. Expanding the search for antivirals which act against SARS-CoV-2 would allow more treatment options for infected patients, accelerate their recovery time, and avoid some serious adverse effects that the limited number of approved medications might cause. In this study, we assess 74 antiviral agents, chloroquine, and hydroxychloroquine inhibitory activity against the virus’s main protease (Mpro), which is essential for its replication. Virtual screening of the compounds has been conducted where the screened ligands were assessed according to their binding energy to the main binding pocket of Mpro. Ten antivirals, in addition to chloroquine and hydroxychloroquine were further studied through molecular docking simulations and assessed for their binding conformations and interactions with the protein’s catalytic dyad residues. Furthermore, molecular dynamics simulations were established to study delavirdine, dolutegravir, raltegravir and vicriviroc for 100 ns. Results show that delavirdine and dolutegravir are excellent candidates that can inhibit the catalytic activity of Mpro. This could significantly reduce patients’ hospitalisation time and the need for secondary measures. [ABSTRACT FROM AUTHOR]

Background: Moringa peregrina (M. peregrina) is an edible, drought-resistant tree that is native to semi-arid countries. It is used as a painkiller in folk medicine. Aims: To study the antinociceptive effects of the leaf extract of M. peregrina in mice. Study Design: Animal experimentation. Methods: We employed thermal (hot plate and tail-immersion tests) and chemical (writhing and formalin tests) pain models in male BALB/c mice (eight animals per group) to investigate the mechanisms involved in the antinociceptive actions of M. peregrina. Additionally, we identified the chemical constituents present in the extract of M. peregrina by using liquid chromatography-mass spectrometry analysis, and predicted the possible active constituents that interact with the receptor based on molecular docking simulations. Results: In the writhing test, 200 mg/kg of M. peregrina extract restricted abdominal cramps by up to 55.97% (p<0.001). Further, it reduced the time of paw-licking in the early and late phases of formalin test by up to 56.8% and 65.5%, respectively, as compared to the percentage inhibitions of 50.5% and 48.4% produced by 30 mg/kg diclofenac sodium in the early and late phases, respectively (p<0.05). This effect was abrogated by yohimbine (1 mg/kg, intraperitoneally), but not by methysergide (5 mg/kg, intraperitoneally), in the late phase only, which indicates that the action of M. peregrina in formalin test is not mediated by 5-HT2 serotonin receptors, but rather via α2-adrenergic receptors. In the hot plate test, but not on tail-immersion test, the high dose (400 mg/kg) of the extract increased the latency time after 30 minutes of its administration. Yohimbine antagonized the action of M. peregrina in the hot plate test. Based on LC-MS analysis, the major constituents found in M. peregrina methanolic extract were chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, and rutin. Depending on the molecular docking results, the activity of M. peregrina extract could be due to the binding of chrysoeriol 7-O-diglucoside, quercetin, and rutin to the α2-adrenergic receptor. Conclusion: Interaction with the α2-adrenergic receptor serves as a possible mechanism of the M. peregrina analgesic effect. [ABSTRACT FROM AUTHOR]

Four benzylidene ketone derivatives were synthesized by reacting 4-nitrobenzaldehyde with several ketone derivatives. The synthesized compounds A, B, C and D had shown antioxidant activity against deoxyribose degradation, while compound C showing the highest activity. The molecular docking simulation indicated that the superior activity of compound C among other compounds can be attributed to the alkyl elongation at ketone chain. [ABSTRACT FROM AUTHOR]

Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 µM. At 11.2 µM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-a (hERa) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERa receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERa. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation. [ABSTRACT FROM AUTHOR]

The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus. [ABSTRACT FROM AUTHOR]

Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of −44.04 and −56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (−66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease. [ABSTRACT FROM AUTHOR]

Selectively targeting cancer cells has been a main challenge in cancer therapy. The purpose is to spare normal cells and minimize side effects. Targeting the antioxidant enzymes ( i.e. GST) for the purpose of selectively killing cancer cells has attracted much attention in the past few decades. The intention of lowering the antioxidant enzymes is "tipping" the ROS concentrations to levels above the cytotoxic threshold. This would result in extensive damage to the cellular macromolecules and organelles leading to cell death. Here we focused on the glutathione S -transferase pi 1 (GSTP1), because it is one of the overexpressed antioxidant enzymes in cancer and has been targeted for the purpose of killing cancer cells. However, most available GSTP1 inhibitors do not show selectivity towards the isozyme. This can potentially lead to many side effects. Therefore, the search for optimal selective GSTP1 inhibitors is still underway. The novelty of this review stems from highlighting the significance of selectively targeting GSTP1. We also addressed the structural feature of the enzyme which challenges the design of novel selective GSTP1 inhibitors. We then provide guidelines to help resolve these challenges to help design future compounds. The first objective of this review is to present a brief literature review to highlight the importance of selectively targeting GSTP1. Briefly, the lack of selectivity towards GSTP1 has resulted in extensive side effects which limited reaching advanced clinical trials. We screened publications on many potential inhibitors, including some that reached phase I and II clinical trials, for their ability to bind with GSTP1, GSTM, and GSTA. All compounds appear to bind different GST isozymes (at least to some extent). The second objective is to present differences in the structures of GST isotypes (GSTP1, GSTM, GSTA) which could allow selectively targeting a certain isotype. Our modelling results highlight the importance of certain structural moieties for better selective binding to GSTP1., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The combination of clopidogrel and acetylsalicylic acid is the standard treatment for atherosclerotic cardiovascular disease. Nonetheless, there is a pressing need for more potent P2Y 12 receptor inhibitors with quicker onset, especially for early intervention in acute myocardial infarction. Integrating computational modeling, i.e. pharmacophore modeling, molecular docking, and dynamics, with empirical data guides the development of effective antiplatelet therapies. This multidisciplinary study employs computational modeling and in-vitro experimental analysis, demonstrating significant inhibition of P2Y 12 activity by two NCI compounds namely: NSC380324 and NSC618163. Both NSC380324 and NSC618163 exhibited a platelet reactivity index (%PRI) of 30.0% and 34.0%, respectively compared to cangrelor that demonstrated superior activity, with a %PRI of 11.0% in platelet vasodilator-stimulated phosphoprotein (VASP) assay. Molecular docking simulations show strong binding affinities of both compounds, along with strong binding interactions at the P2Y 12 binding site. Importantly, molecular dynamics simulations highlight the influence of receptor dynamics on practical efficacy, suggesting that NSC380324, a promising P2Y 12 antagonists indicated by its excellent stability profiles at the binding pocket of P2Y 12 , its hydrogen-bond interactions occupancies and the average MM-PBSA total binding energy of -38.17 kcal/mol, require further structural optimization and in-vivo studies to realize their full potential for clinical application.

Aims: This study aimed at the synthesis of several spiro[benzofuran-3,3'-pyrroles] derivatives by a three-component reaction conducted by mixing DMAD, N-bridgehead het-erocycles, and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. Moreover, in vitro evaluation of their cytotoxicity affinities against FMS-like tyrosine kinase 3 was carried out., Objectives: The objective of this study was to use a one-pot, three-component reaction to synthesize a novel set of spiro[benzofuran-3,3'-pyrroles] derivatives., Methods: A novel set of spiro[benzofuran-3,3'-pyrroles] ((11-13)a-e) was synthesized by a one-pot three-component reaction involving dimethyl acetylenedicarboxylate, N-bridgehead heterocycles and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. The compounds were analyzed using NMR 1H, 13C, 2D-NMR (COSY, HMQC, HMBC), and HRMS. Docking simulations were conducted to elucidate the anticancer activity of synthe-sized compounds on FLT3 protein, with Gilteritinib as a reference for comparison., Results: This study demonstrated the successful design, synthesis, and biological evaluation of spiro[benzofuran-3,3'-pyrroles] derivatives as FLT3 inhibitors for AML treatment. The synthesized compounds demonstrated promising binding affinities and significant inhibitory activity against FLT3 kinase. The inhibitors (11a, 11b, 11c, 12d, and 12e) exhibited excellent selectivity profiles against FLT3. Particularly, compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM)., Conclusion: Fifteen new synthetic spiro[benzofuran-3,3'-pyrroles] were prepared, character-ized, and evaluated for cytotoxicity affinities against FMS-like tyrosine kinase 3. Compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM), making it a promising candidate for further development as a therapeutic option for AML treatment. These findings lay the groundwork for further optimization and development of spiro[benzo-furan-3,3'-pyrroles] derivatives as potential therapeutics for AML treatment. Further studies are needed to explore their efficacy and safety profiles in preclinical and clinical settings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

P2Y 12 has a key role in platelet aggregation and thrombus formation via an ADP-induced platelet activation mechanism. Recently, P2Y 12 antagonists have become of great interest in the clinical management of antithrombotic therapy. In light of this, we explored the pharmacophoric space of P2Y 12 using structure-based pharmacophore modelling. Subsequently, genetic algorithm and multiple linear regression analyses were conducted to select the best combination of physicochemical descriptors and pharmacophoric models to create useful predictive quantitative structure-activity relationship (QSAR) equation ( r 2 = 0.9135, r (adj) 2 = 0.9147, r (PRESS) 2 = 0.9129, LOF = 0.3553). One pharmacophoric model emerged in the QSAR equation and was validated by analysing receiver operating characteristic (ROC) curves. The model was then used to screen 200 000 compounds from the National Cancer Institute (NCI) database. The top-ranked hits were in vitro tested, where their IC 50 's range between 4.20 to 35.00 μM when measured via the electrode aggregometry assay. Whilst, the VASP phosphorylation assay showed 29.70% platelet reactivity index for NSC618159, which is superior to that of ticagrelor., Competing Interests: The authors have no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

In the title compound, C(18)H(13)F(2)NO(5)S(2), the complete mol-ecule is generated by a crystallographic inversion centre, and the O atom and the N-H group attached to the central ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 64.03 (6)°. In the crystal, N-H⋯O, C-H⋯F and C-H⋯O inter-actions link the mol-ecules into a three-dimensional network.

The complete mol-ecule of the title compound, C(20)H(19)NO(5)S(2), is generated by a crystallographic twofold axis and the O atom and N-H group attached to the central benzene ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 56.91 (5)° and that between the terminal benzene rings is 29.80 (5)°. In the crystal, N-H⋯O hydrogen bonding links the mol-ecules into sheets lying parallel to the ab plane.