Search

As a complex composite material, tire rubber has always presented significant environmental and waste management concerns due to its non-biodegradability and accumulation in landfills. The devulcanization of tire rubber has emerged as a historical challenge in the field of sustainable rubber engineering since Goodyear invented cross-linking in 1839. This review provides a comprehensive analysis of waste tire recycling processes, focusing on the sources, legislation, management strategies, and utilization across different regions. It explores the multifaceted challenges of devulcanizing rubber, with a specific focus on transitioning from ground tire rubber to the concept of multi-decrosslinking: sulfur bridge breakage, rubber chain depolymerization and micro-nano sized core-shell carbon black. Ideal devulcanization has restricted the release of reinforcing fillers, resulting in devulcanized rubber mainly containing dozens of micron particles, which hinder the wide usage of devulcanized rubber. This review comprehensively assesses the current state-of-the-art techniques for tire rubber devulcanization, including physical, chemical and biological methods. It explores the intricacies of ground tire rubber as a starting material, structural evolution of ground tire rubber during the devulcanization process and the associated challenges in achieving efficient devulcanization while retaining desirable mechanical properties. Furthermore, through an in-depth analysis of recent advancements, limitations and prospects, this paper offers a complete understanding of the challenges faced in tire rubber devulcanization. Considering the technical and environmental aspects of these processes, this work contributes to multi-decrosslinking, the ongoing discourse on sustainable materials development and circular economy initiatives, which pave the way for future innovations in the field of rubber recycling. more...

Malaria remains one of the great killers in tropical regions of the world due to the transmission of the Plasmodium parasite by the bites of the female mosquito Anopheles. The resistance of this species to synthetic insecticides contributes to an increase in the incidence of malaria and therefore necessitates the development of new potent and eco-friendly insecticides. In this study, twelve previously reported limonoids from four Entandrophragma species collected in Cameroon have been computationally evaluated for their Anopheles gambiae AChE inhibitory activity. The docking procedure was carried out through Molecular Operating Environment 2019.01 (MOE), while the UCSF Chimera program was used to model the docking results based on interactions between proteins and ligands, and molecular dynamics trajectories were analyzed using the GROMACS 2021.1 tool. Entandrophragmin and encandollens B and C with docking scores ranging from −6.45 to −7.28 kcal/mol were the most promising hits compared to the reference azadirachtin (−6.22 kcal/mol) and were further evaluated for their mechanism of action. Subsequent evaluation classified encandollen C as the best candidate for the development of new potent eco-friendly insecticides based on its lower average RMSD and RMSF and its compactness over a 150 ns duration with acetylcholinesterase. more...

The increasing prevalence of antibiotic resistance poses a significant global risk to public health. Therefore, there is an urgent necessity to discover innovative antibacterial materials. In this study, we introduced a novel synthesis method that yielded 18 unique di-cationic ionic liquids (DILs), intricately crafted through a fusion of quaternization and metathesis reactions. These innovative compounds boasted imidazolium, pyridinium, and quaternary ammonium as their cationic constituents, accompanied by acetate and bisulfate ions as their anionic counterparts. The incorporation of spacer chains, specifically trans-1,4-dibromo-2-butene and α, α′-dibromo-p-xylene, facilitated the synthesis of these di-cations. Thorough characterization of the synthesized DILs was conducted using advanced spectroscopic techniques, including FTIR and nuclear magnetic resonance, ensuring a comprehensive understanding of their structural attributes. The central objective of this research was to assess the effectiveness of these DILs in combating a diverse spectrum of resilient bacterial strains commonly encountered in various environmental settings. This evaluation encompassed both gram-positive and gram-negative species. more...

Introduction: Adiantum aleuticum (A. aleuticum) belongs to a medicinally important genus Adiantum. Different species of genus Adiantum are traditionally used as anti-diabetic, analgesic, anti-inflammatory, and antifungal remedy. A. aleuticum is scientifically unexplored species of genus Adiantum. The current study aimed to reveal the medicinal potential of A. aleuticum. In addition to preliminary phytochemical investigation, GC–MS analysis and computational studies (In-silico docking and ADME analysis) were also performed. Methods: Different biological activities like enzyme inhibition, antimicrobial (antibacterial and antiviral), anti-inflammatory, and thrombolytic activity were performed by various In-vitro assays. Antioxidant potential was assessed by DPPH and ABTS methods. Results: The findings of phytochemical screening revealed that highest TPC, TFC and TTC were observed in AME (290 ± 1.12 mg G.A Eq./g D.E ± S.D, 424 ± 0.559 mg Q. Eq./g D.E ± S.D, 335 ± 0.48 mg T.A Eq./g D.E ± S.D) respectively. The antioxidant potential was exhibited by AME via DPPH and ABTS (302 ± 0.66, 315 ± 0.52 mg A.A Eq./g D.E ± S.D) respectively. The results of enzyme inhibition activity revealed that AME strongly inhibited α-amylase (73 %) & α-glucosidase (74 %). Significant antiviral and antibacterial activities were shown by AME and its all fractions. AME also exhibited maximum thrombolytic activity (70 ± 0.60 %clot lysis) in comparison to Streptokinase (86 ± 0.9 % clot lysis). The maximum anti-inflammatory activity was observed in AME with %IPD range (40–79 %) for various fractions. GC–MS analysis of AME tentatively identified 37 bioactive phytoconstituents. The In-silico molecular modelling was done for the identified compounds by GC/MS for the evaluation of binding affinity and binding interactions between the ligands and enzyme followed by ADME analysis of selected phytoconstituents with best docking scores. MD simulation was done for Solasonine. Conclusion: Conclusively, A. aleuticum has good antidiabetic, antimicrobial and thrombolytic potential. It can be explored further for other biological activities and may provide basis for the isolation of natural anti-diabetic, anti-inflammatory, thrombolytic, antioxidant and antibacterial compunds with potential for serving as promising leads for drug development. more...

Abstract Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4. Molecular structures were encoded into bit arrays, serving as molecular fingerprints, which were subsequently analyzed using the Bayesian network algorithm to identify patterns for screening the data. The shortlisted hits obtained via machine learning protocols were further validated by Molecular Docking and via ADME and Toxicity predictions. The shortlisted compounds were then subjected to MD Simulations of the membrane-bound FFAR4-ligand complexes for 100 ns each. Molecular analyses, encompassing binding interactions, RMSD, RMSF, RoG, PCA, and FEL, were conducted to scrutinize the protein–ligand complexes at the inter-atomic level. The analyses revealed significant interactions of the shortlisted compounds with the crucial residues of FFAR4 previously documented. FFAR4 as part of the complexes demonstrated consistent RMSDs, ranging from 3.57 to 3.64, with minimal residue fluctuations 5.27 to 6.03 nm, suggesting stable complexes. The gyration values fluctuated between 22.8 to 23.5 nm, indicating structural compactness and orderliness across the studied systems. Additionally, distinct conformational motions were observed in each complex, with energy contours shifting to broader energy basins throughout the simulation, suggesting thermodynamically stable protein–ligand complexes. The two compounds CHEMBL2012662 and CHEMBL64616 are presented as potential FFAR4 agonists, based on these insights and in-depth analyses. Collectively, these findings advance our comprehension of FFAR4’s functions and mechanisms, highlighting these compounds as potential FFAR4 agonists worthy of further exploration as innovative treatments for metabolic and immune-related conditions. more...

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (triple-negative breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281 µM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282 µM for (6d), against MDA-MB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values ranging from 16.8 ± 0.37 µM to 31.3 ± 0.86 µM against MDA-MB-231 and 13.5 ± 0.92 µM to 24.2 ± 0.21 µM against HepG2. In particular, spirooxindole derivatives incorporating 2,4-dichlorophenyl moiety were the most active, with an IC50 of 16.8 ± 0.37 µM for (9h) against MDA-MB-23 and 13.5 ± 0.92 µM for (9i) against HepG2. Interestingly, the IC50 of compound (6c) (7.2 µM) exhibited better activity than that of Sorafenib (positive control) (9.98 µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site. more...

Introduction: The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance. Extensive research in past has uncovered a number of inhibitors, while the ISO-1, or (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester being recognized as a benchmark standard so far. Recent work by Yang and coworkers identified five promising dietary flavonoids, with superior activity compared to the standard ISO-1. Nevertheless, the exact atomic-level inhibitory mechanism is still elusive.Methods: To improve the dynamic research, and rigorously characterize, and compare molecular signatures of MIF complexes with ISO-1 and flavonoids, principal component analysis (PCA) was linked with molecular dynamics (MD) simulations and binding free energy calculations.Results: The results suggest that by blocking the tautomerase site these small molecule inhibitors could modify the MIF activity by disrupting the intrinsic dynamics in particular functional areas. The stability matrices revealed the average deviation values ranging from 0.27–0.32 nm while the residue level fluctuations indicated that binding of the selected flavonoids confer enhanced stability relative to the ISO-1. Furthermore, the gyration values extracted from the simulated trajectories were found in the range of 1.80–1.83 nm.Discussion: Although all the tested flavonoids demonstrated remarkable results, the one obtained for the potent inhibitors, particularly Morin and Amentoflavone exhibited a good correlation with biological activity. The PCA results featured relatively less variance and constricted conformational landscape than others. The stable ensembles and reduced variation in turns might be the possible reasons for their outstanding performance documented previously. The results from the present exploration provide a comprehensive understanding of the molecular complexes formed by flavonoids and MIF, shedding light on their potential roles and impacts. Future studies on MIF inhibitors may benefit from the knowledge gathered from this investigation. more...

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12 μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32 μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87–18.5 μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8 μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2 μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2. more...

Erythropoietin (Epo), a glycosylated protein categorized as a member of the cytokine family, is responsible for the modulation of erythrogenesis. Besides this, the nonhaematopoietic effects of Epo are associated with tissue-protective activity via an antiapoptotic pathway. This function of Epo is linked with its heterodimeric form, i.e. EpoR/βcR belonging to the cytokine family as well. Both receptors are dissected into three domains: extracellular (also known as ligand-binding domain), transmembrane and cytoplasmic domain. The transmembrane and cytoplasmic domains are assumed to play a paramount role in dimerization and tissue protection. However, the tertiary structure of cytoplasmic domains of both EpoR and βcR was not reported in the literature. Inspired by the potential therapeutic applications, we aimed to investigate the interaction pattern of EpoR/βcR using in silico tools. Cytoplasmic domains of EpoR and βcR were modelled, structural refinement was carried out through Rosetta, and these were then quality verified by well-known quality matrices. The observed results were found to be structurally consistent with the amenable geometry showing stereochemical sustainability. The modelled cytoplasmic domains were then successfully merged with the remaining domains (extracellular and transmembrane domains) of the respective receptors through MOEv2019.01 and Modeller. The complete structures of EpoR and βcR were subjected to geometry optimization and energy minimization via dynamic studies. The refined structures were subjected to protein–protein docking to yield the heterocomplex. Here, we report on the optimized structure coordinates of EpoR/βcR, the plausible electrostatic interactions involving G191, V206, T214, S241, T244, E336, R337, M342, G348, T349, E362 and K373 of EpoR and D336, S337, Y338, K333, R391, M426, H494, Q495, S717, S722, Y750 and G758 of βcR. Subsequently, we performed screening utilizing the StraPep database to identify Epo mimetic agents with the potential to enhance their tissue-protective effects. Following the virtual screening, four hits (4HQX, 4XO8, 1TPO and 3EZM) were obtained based on the binding affinity and protein–ligand interaction fingerprinting (PLIF). The stability exhibited by the four selected peptides in the binding site of the EpoR/βcR heterocomplex became visible during visual inspection. We propose that the presented model can be harnessed for future characterization studies. more...

Introduction: Ailanthus altissima is an indigenous plant known for various remedial properties. The present study aimed to evaluate the neuroprotective potential of methanolic extract Ailanthus altissima (AA) bark as current scientific trend is searching plant for neurodegenerative diseases, worldwide. Methodology: In in-vitro experiments, the AA was analyzed for phenols, flavonoids, antioxidative and cholinesterase inhibitory properties with subsequent detailed characterization for secondary metabolites. The in-vivo neurological effects were evaluated in rats through behavioral assessment for anxiety and memory after chronic administration (28 days) of 50–200 mg/kg of AA. At the end of behavior studies, isolated brains were biochemically tested to determine antioxidant enzyme activity. Results: AA was found rich in phenols/flavonoids and active in radical scavenging with the presence of 13 secondary metabolites in UHPLC-MS analysis. The AA yielded anxiolytic effects dose-dependently in the open field, light/dark and elevated-plus maze tests as animals significantly (P more...

Croton bonplandianus, a natural source traditionally used for treating various illnesses, including rheumatoid arthritis, was evaluated in this study. The effects of ethanolic extracts (CBEE) and aqueous fractions (CBAF) of C. bonplandianus leaves on arthritis-induced inflammation were studied using an albino rat model of inflammation induced by Freund's complete adjuvant. Eight test groups (n = 5 per group) and one vehicle control were used to evaluate the antiarthritic effects of different doses of CBEE and CBAF (125 mg.kg−1, 250 mg.kg−1, and 500 mg.kg−1) on days 5, 10, 15, and 20 compared to arthritic and vehicle controls. Arthritis severity was assessed using macroscopic arthritis grading, histological analysis, body weights, and paw thickness. CBEE and CBAF were found to reduce the prevalence of arthritis, increase body weight, and decrease paw inflammation compared to the vehicle control group by the 23rd day. In addition, they showed no effect on biochemical parameters, but a significant difference (p more...

AbstractMost of the drugs are hydrophobic and have low water solubility, therefore posing issues in their absorption and bioavailability. Nonionic surfactants improve the solubility of hydrophobic drugs by entrapping them in their lipid bilayers. Two nonionic surfactants NODNH-16 and NODNH-18 are synthesized and characterized using different techniques i.e. EI-MS, 1H NMR, and FTIR. These newly synthesized surfactants were screened for blood hemolysis assay and cell toxicity studies using the NIH/3T3 cell line to assess their biocompatibility. Then amphotericin B was loaded into niosomal vesicles, and the drug entrapment efficiency of these surfactants was measured using UV–visible spectroscopy. The morphology of drug-loaded niosomes of synthesized surfactants was investigated using AFM, and their size, polydispersity, and zeta potential were measured with the Zetasizer instrument. Finally, a simulation study was performed to determine the pattern of self-assembly of the synthesized amphiphiles. Both synthesized nonionic surfactants showed good entrapment efficiency of 60.65 ± 2.12% and 68.45 ± 2.12%, respectively. It was also confirmed that both these synthesized nonionic surfactants were safe and biocompatible and showed less blood hemolysis (i.e. 21.13 ± 2.11% and 23.32 ± 2.45%) and higher 3T3 cells’ viability at 150 µg/mL concentration as compared to Tween®-80. The antifungal potential of amphotericin B-loaded niosomes has been evaluated against unicellular multi-fungal species, which showed a promising potential for fungicidal activity. These results are substantiated by constructing a safe vehicle system for drug delivery. more...

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids. more...

Currently, acetylcholinesterase (AChE) inhibiting drugs in clinical use, such as tacrine, donepezil, rivastigmine, and galanthamine, are associated with serious side effects and short half-lives. In recent years, numerous phytochemicals have been identified as inhibitors of cholinesterases with potential applications in the management of Alzheimer’s disease (AD). In this study three natural coumarins, 2′-O-ethylmurrangatin (1), murranganone (2), and paniculatin (3) isolated previously by our group from the leaves of Murraya paniculata, were tested against the two cholinesterases (ChE) enzymes, AChE and butyrylcholinesterase (BChE) using in vitro assay. Molecular docking was performed to highlight the structural properties that contribute to the molecular recognition pattern in the inhibition of ChE and the structural differences resulting in the selectivity of these compounds toward AChE. Classical enzyme inhibition kinetics data suggested that compounds 2 and 3 were potent inhibitors of AChE and BChE, while 1 was found inactive against both enzymes. The findings from molecular docking studies revealed the competitive and non-competitive inhibition mechanisms of compounds 2 and 3 against both enzymes. Molecular docking and simulations have revealed that hydrogen bonding, mediated by ketone and hydroxyl functionalities in various positions, significantly contributes to the binding of the inhibitor to the receptor. According to MD simulation studies, the stability of the ligand-AChE complex for the most active compound (3) is found to be comparable to that of the widely used drug Tacrine. In addition, to evaluate the drug-likeness of compounds, in silico ADME evaluation was performed, and the compounds presented good ADME profiles. Data suggested that the coumarin nucleus having diverse side chains at the C-8 position can serve as a potential inhibitor of cholinesterases and can act as a lead to develop a new semisynthetic drug for the treatment of AD. more...

Human serum albumin (HSA) is a multi-domain macromolecule with diverse ligand binding capability because of its ability to allow allosteric modulation despite being a monomeric protein. Physiologically, HSA act as the primary carrier for various exogenous and endogenous compounds and fatty acids, and alter the pharmacokinetic properties of several drugs. It has antioxidant properties and is utilized therapeutically to improve the drug delivery of pharmacological agents for the treatment of several disorders. The flexibility of albumin in holding various types of drugs coupled with a variety of modifications makes this protein a versatile drug carrier with incalculable potential in therapeutics. This review provides a brief outline of the different structural properties of HSA, and its various binding sites, moreover, an overview of the genetic, biomedical, and allosteric modulation of drugs and drug delivery aspects of HSA is also included, which may be helpful in guiding advanced clinical applications and further research on the therapeutic potential of this extraordinary protein. more...

Abstract Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets. more...

Interleukin-2 (IL-2) is involved in the activation and differentiation of T-helper cells. Uncontrolled activated T cells play a key role in the pathophysiology by stimulating inflammation and autoimmune diseases like arthritis, psoriasis and Crohn’s disease. T cells activation can be suppressed either by preventing IL-2 production or blocking the IL-2 interaction with its receptor. Hence, IL-2 is now emerging as a target for novel therapeutic approaches in several autoimmune disorders. This study was carried out to set up an effective virtual screening (VS) pipeline for IL-2. Four docking/scoring approaches (FRED, MOE, GOLD and Surflex-Dock) were compared in the re-docking process to test their performance in producing correct binding modes of IL-2 inhibitors. Surflex-Dock and FRED were the best in predicting the native pose in its top-ranking position. Shapegauss and CGO scoring functions identified the known inhibitors of IL-2 in top 1, 5 and 10 % of library and differentiated binders from non-binders efficiently with average AUC of > 0.9 and > 0.7, resp. The applied docking protocol served as a basis for the VS of a large database that will lead to the identification of more active compounds against IL-2. more...

The pandemic of COVID-19, caused by SARS-CoV-2, has globally affected the human health and economy. Since the emergence of the novel coronavirus SARS-CoV-2, the life-threatening virus continues to mutate and evolve. Irrespective of acquired natural immunity and vaccine-induced immunity, the emerging multiple variants are growing exponentially, crossing the territorial barriers of the modern world. The rapid emergence of SARS-CoV-2 multiple variants challenges global researchers regarding the efficacy of available vaccines and variant transmissibility. SARS-CoV-2 surface-anchored S-protein recognizes and interacts with the host-cell ACE2, facilitating viral adherence and entrance into the cell. Understanding the interfacial interactions between the spike protein of SARS-CoV-2 variants and human ACE2 receptor is important for the design and development of antiviral therapeutics against SARS-CoV-2 emerging variants. Despite extensive research, the crucial determinants related to the molecular interactions between the spike protein of SARS-CoV-2 variants and host receptors are poorly understood. Thus, in this study, we explore the comparative interfacial binding pattern of SARS-CoV-2 spike RBD of wild type, Delta, and Omicron with the human ACE2 receptor to determine the crucial determinants at the atomistic level, using MD simulation and MM/GBSA energy calculations. Based on our findings, the substitution of Q493R, G496S, Q498R, and Y505H induced internal conformational changes in Omicron spike RBD, which leads to higher binding affinity than Delta spike RBD with the human ACE2 receptor, eventually contributing to higher transmission and infectivity. Taken together, these results could be used for the structure-based design of effective antiviral therapeutics against SARS-CoV-2 variants. more...

Rational design for a new spiroxindoles, combined with a benzimidazole scaffold to identify a new murine double minute two (MDM2) inhibitor was synthesized and characterized. The desired spiroxindoles were achieved via a [3+2] cycloaddition reaction approach which afforded the cycloadducts with four asymmetric centers separated in an excellent regioselective and diastereoselective compound. The separated spiroxindoles were subjected to a set of biochemical assays including an NCI cell panel assay, MTT assay, and MDM2 binding analysis by a microscale thermophoresis assay. The anticancer reactivity for the tested compounds showed IC50 (µM) in the range between 3.797–6.879 µM, and compound 7d with IC50 = 3.797 ± 0.205 µM was the most active candidate between the series. The results showed promising results that identified that compound 7a could be inhibited the MDM2 with KD = 2.38 μm. Compound 7a developed a network of interactions with the MDM2 receptor studied in silico by molecular docking. more...

The kinetics of hydrolysis of fluvoxamine maleate (FLV) has been investigated over the pH range 1.0–12.0 at 40, 60 and 80 °C. FLV degradation follows pseudo-first-order kinetics which is consistent with the kinetics of drugs that are not readily dissolved in aqueous medium. The hydrolytic degradation rate constant (kobs) range from 0.92 (pH 6.0) to 13.8 × 10−4 min−1 (pH 1.0). The kobs represents the sum of six different degradation rate constants; the kH has been found to be higher than kOH. The FLV exhibits a typical rate- pH profile with a flat bottom over the pH range 3.0–6.0 which indicates its maximum stability at pH 6.0. Ten FLV degradants have been predicted by Zeneth software and among them four degradation products (D1, D2, D3 and D4) have been identified in degraded samples. The in-silico pharmacokinetics and toxicity of degradation products have been determined using Swiss ADME and admetSAR software. The toxicity profile reveals that D2 is both AMES toxic and carcinogenic while the rest of the products are non-AMES toxic and non-carcinogenic. All of the degradation products are high in causing fish toxicity thus their presence in pharmaceutical waste is alarming for environmental safety. Keywords: Fluvoxamine, Degradation kinetics, In-silico correlation, Pharmacokinetic, Toxicity profile more...

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a–k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM). more...

The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16–24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains. more...

Currently the discovery and development of potent β-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives 1–27 were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds 1–27 were then evaluated for their β-glucuronidase inhibitory activity, and among them, compound 24 (IC50 = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC50 = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and β-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent β-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products. more...

Inhibitor of kappa B kinase subunit β (IKKβ) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds. more...

Acetylcholinesterase (AChE) inhibitors and calcium channel blockers are considered effective therapies for Alzheimer’s disease. AChE plays an essential role in the nervous system by catalyzing the hydrolysis of the neurotransmitter acetylcholine. In this study, the inhibition of the enzyme AChE by Sarcorucinine-D, a pregnane type steroidal alkaloid, was investigated with experimental enzyme kinetics and molecular dynamics (MD) simulation techniques. Kinetics studies showed that Sarcorucinine-D inhibits two cholinesterases—AChE and butyrylcholinesterase (BChE)—noncompetitively, with Ki values of 103.3 and 4.66 µM, respectively. In silico ligand-protein docking and MD simulation studies conducted on AChE predicted that Sarcorucinine-D interacted via hydrophobic interactions and hydrogen bonds with the residues of the active-site gorge of AChE. Sarcorucinine-D was able to relax contractility concentration-dependently in the intestinal smooth muscles of jejunum obtained from rabbits. Not only was the spontaneous spasmogenicity inhibited, but it also suppressed K+-mediated spasmogenicity, indicating an effect via the inhibition of voltage-dependent Ca2+ channels. Sarcorucinine-D could be considered a potential lead molecule based on its properties as a noncompetitive AChE inhibitor and a Ca2+ channel blocker. more...

Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in cases of chronic dental caries, inhibiting bacterial biofilm assembly should prevent demineralization of tooth enamel, thereby preventing tooth decay. A high throughput screening was performed in the present study to identify small molecule inhibitors of S. mutans glycosyltransferases. Multiple pharmacophore models were developed, validated with multiple datasets, and used for virtual screening against large chemical databases. Over 3000 drug-like hits were obtained that were analyzed to explore their binding mode. Finally, six compounds that showed good binding affinities were further analyzed for ADME (absorption, distribution, metabolism, and excretion) properties. The obtained in silico hits were evaluated for in vitro biofilm formation. The compounds displayed excellent antibiofilm activities with minimum inhibitory concentration (MIC) values of 15.26–250 µg/mL. more...

Rhinacanthins-rich extract (RRE) from Rhinacanthus nasutus leaf and its marker compounds namely rhinacanthin-C, rhinacanthin-D and rhinacanthin-N were evaluated for α-glucosidase inhibitory activity. RRE (IC50 value of 25.0 µg/mL) exhibited α-glucosidase inhibitory activity almost equivalent to that of rhinacanthin-C (IC50 value of 22.6 µg/mL) but stronger than that of rhinacanthin-D (IC50 value of 71.5 µg/mL) and the standard drug, acarbose (IC50 value of 395.4 µg/mL), while rhinacanthin-N was inactive. Kinetic studies revealed that both RRE and rhinacanthin-C exhibited noncompetitive α-glucosidase inhibitory activity, while combinations of either RRE or rhinacanthin-C with acarbose at low concentrations (¼IC50, ½IC50 and IC50) showed a synergistic inhibitory effect. In silico studies identified the binding mode of rhinacanthin-C highlighting the formation of both polar and apolar contacts of ligand with α-glucosidase. The present study provides the first evidence that RRE containing rhinacanthin-C as the major compound, could find application as an α-glucosidase inhibitor. more...

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1-(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors. more...

In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5–6 and 8a–8b. The compound 5 exhibits an exceptional IC50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research. more...