High Inhibitory Potency Research Articles

Virtual screening of antiviral peptides as novel blockers of human papillomavirus 16

Human papillomaviruses (HPVs) contribute to 5% of cancers, yet there is a lack of specific antiviral agents targeting HPV infection. Antiviral peptides (AVPs) present a promising alternative to conventional therapeutics. This study aims to explore the use of AVPs against the HPV16 E6 oncoprotein through virtual screening. The potential binding pocket of the E6 oncoprotein was determined, and using the antimicrobial CAMPR4 database 18 AVPs were shortlisted. These AVPs were then docked to the E6 oncoprotein using the HawkDock server, followed by dynamic simulation. Among the AVPs tested, AVP18, AVP10, and AVP7 demon­strated the highest inhibitory potential against the E6 oncoprotein. AVP18 exhibited more non-bonded contacts, hydrogen bonds, and electrostatic forces. Dynamics simulation confirmed the stability of the complexes formed by these top AVPs with E6. This research suggests that AVP7, AVP10, and AVP18 are promising lead candidates for blocking HPV16 by inhibiting the E6 oncoprotein. Keywords: antiviral peptides, docking, dynamics simulation, E6 oncoprotein, human papillomavirus

Investigation of pivalic acid-derived organotin(IV) carboxylates: Synthesis, structural insights, interaction with biomolecules, and computational studies

Herein, six homoleptic and heteroleptic tri-organotin(IV) complexes (1–6) of pivalic acid (HL) were synthesized using 2,2′-bipyridine (bipy) and organotin(IV) chlorides, with a general formula of R3SnL/R3SnLbipy, where R = CH3, C4H9, and C6H5. The structure of the complexes was established in the solid phase via FT-IR spectroscopy and in solution through multinuclear NMR spectroscopy. The variety of coordination modes was implemented by the carboxylate group of pivalic acid, which is reflected in the FT-IR data and also supported by the single crystal XRD analysis for complex 5. The single crystal data revealed the presence of a five-coordinated distorted trigonal bipyramidal geometry for complex 5. The structural and electronic details of the complexes were also evaluated by the application of density functional theory through the Lanl2DZ basis set. The ability of complexes to inhibit the AChE and BChE was assessed in vitro as well as theoretically through molecular docking studies and the results were promising. The complexes 4 and 5 showed high inhibitory potency and could be a potential drug candidate. The DNA binding mode of the complexes was studied using UV–Vis spectroscopy and cyclic voltammetry. The findings revealed that these complexes readily intercalate into DNA via a spontaneous process. Additionally, an effective binding of the complexes with surfactant cetyl trimethyl ammonium bromide (CTAB) through a spontaneous process also proved them valuable in pharmacology.

Protein hydrolysates with ACE-I inhibitory activity from amaranth seeds fermented with Enterococcus faecium-LR9: Identification of peptides and molecular docking

One of the causes of hypertension is the activity of angiotensin-I converting enzyme (ACEI), making its inhibition a crucial strategy for controlling the disease. Protein hydrolysates are a known source of bioactive peptides that contribute to ACE-I inhibition. This study aims to evaluate the ACE-I inhibitory activity of amaranth seed hydrolysates after fermentation with Enterococcus faecium-LR9 and to compare it with Leuconostoc mesenteroides-18C6 and enzymatic hydrolysis (Alcalase®). The fermentation strategy with LR9 proved to be more effective in inhibiting ACE-I (79.1 ± 2.6 %) in vitro compared to 18C6 (68.0 ± 9.8 %) and enzymatic hydrolysis (69.4 ± 1.2 %). Consequently, these protein hydrolysates were subjected to in silico analysis, identifying 125 novel peptides. Bioinformatics and molecular docking analyses revealed 10 peptides with high ACE-I inhibitory potential. Among them, the IFQFPKTY and VIKPPSRAW peptides stood out. Therefore, E. faecium-LR9 is a promising strain for the release of bioactive peptides from seed storage proteins.

In silico DFT and molecular modeling of novel pyrazine-bearing thiazolidinone hybrids derivatives: elucidating invitro anti-cancer and urease inhibitors.

In the present work, one of the leading health issues i.e.cancer was targeted by synthesizing and biologically investigating the potential of pyrazine-based thiazolidinone derivatives (1-13). The basic structure of the synthesized compounds was determined using a variety of spectroscopic techniques, including 1H NMR, 13C NMR, and HREI-MS. These scaffolds were studied for their biological profiles as anti-cancer as well as anti-urease agents. The biological effectiveness of these compounds was compared using the reference tetrandrine (IC50=4.50±0.20 µM) and thiourea (IC50=5.10±0.10 µM), respectively. Among novel compounds, scaffold 3, 6, 7 and 10 demonstrated an excellent potency with highest inhibitory potential (IC50=1.70±0.10 and 1.30±0.20 µM), (IC50=4.20±0.10 and 5.10±0.30 µM), (IC50=2.10±0.10 and 3.20±0.20 µM) and (IC50=2.70±0.20 and 4.20±0.20 µM), respectively, out of which scaffold 3 emerged as the leading compound due to the presence of highly reactive-CF3 moiety which interacts via hydrogen bonding. Molecular docking investigations of the potent compounds was also carried out which revealed the binding interactions of ligands with the active sites of enzyme. Moreover, the electronic properties, nucleophilic and electrophilic sited of the lead compounds were also studied under density functional theory (DFT).

Bioassay guided isolation and compounds identification of the anti-diabetic fractions of (rosemary) Rosmarinus officinalis leaves extract

BackgroundDiabetes mellitus is a metabolic disease characterized by prolonged elevated blood glucose levels. It is a common health problem with a high mortality and morbidity to the human race. A number of medicinal plants such as rosemary (Rosmarinus officinalis) have been used for the treatment of diabetes. Most of the anti-diabetic conventional drugs have been found to have some side effects and there is therefore need to explore new sources of anti-diabetic drugs. The aim of the current study was to investigate the possibility of getting anti-diabetic compounds from R. officinalis that can be used as leads for drug discovery.MethodologyR. officinalis leaves were macerated in 50% methanol in dichloromethane and the crude extract fractionated by column chromatography. The obtained fractions were subjected to an in-vitro alpha-amylase inhibition assay. The anti-hyperglycemic potential of the fractions was evaluated in diabetic induced Wistar rats. The most potent fractions were analyzed by gas chromatography-mass spectrophotometry (GC-MS) for identification of the compounds.ResultsA total of 21 chromatographic fractions were assembled with different alpha- amylase inhibition activity. Eleven of the fractions had more than 30% alpha-amylase inhibition activity. The ethyl acetate fraction had the highest inhibition potential (LC50 of 2.8 μg/mL). The anti-diabetic assay in rats showed that fractions (F1) and (F4) had highest blood glucose reduction of 44.5 ± 0.4 and 52.8 ± 1.3%, respectively (p < 0.05). GC-MS analysis of fractions F1 and F4 showed the presence of 21 and 23 compounds in F1 and 23, respectively.ConclusionThis study has demonstrated that R. officinalis crude extract fractions obtained from 50% methanol in dichloromethane possesses alpha-amylase inhibitory and anti-hyperglycemic activities as well as secondary metabolites with varying chemical structures. The hexane and hexane/ethyl acetate (8/2) fractions showed most potent alpha-amylase inhibition with high anti-hyperglycemic activity giving hope of a possibility of obtaining lead compounds for new anti-diabetic drugs.

Molecular hybridization assisted multi-technique approach for designing USP21 inhibitors to halt catalytic triad-mediated nucleophilic attack and suppress pancreatic ductal adenocarcinoma progression: A molecular dynamics study

AimsPancreatic cancer, the 12th-most common cancer, globally, is highly challenging to treat due to its complex epigenetic, metabolic, and genomic characteristics. In pancreatic ductal adenocarcinoma, USP21 acts as an oncogene by stabilizing the long isoform of Transcription Factor 7, thereby activating the Wnt signaling pathway. This study aims to inhibit activation of this pathway through computer-aided drug discovery. Accordingly, four libraries of compounds were designed to target the USP21's catalytic domain (Cys221, His518, Asp534), responsible for its deubiquitinating activity. Main methodsUtilizing an array of computer-aided drug design methodologies, such as molecular docking, virtual screening, principal component analysis, molecular dynamics simulation, and dynamic cross-correlation matrix, the structural and functional characteristics of the USP21-inhibitor complex were examined. Following the evaluation of the binding affinities, 20 potential ligands were selected, and the best ligand was subjected to additional molecular dynamics simulation study. Key findingsThe results indicated that the ligand-bound USP21 exhibited reduced structural fluctuations compared to the unbound form, as evident from RMSD, RMSF, Rg, and SASA graphs. ADMET analysis of the top ligand showed promising pharmacokinetic and pharmacodynamic profiles, good bioavailability, and low toxicity. The stable conformations of the proposed drug when bound to their target cavities indicate a robust binding affinity of −9.3 kcal/mol. The drug exhibits an elevated pKi value of 6.82, a noteworthy pIC50 value of 5.972, and a pKd value of 6.023 proving its high affinity and inhibitory potential towards the target. SignificanceIn-vitro testing of the top compound (MOLHYB-0436) could lead to its use as a potential treatment for pancreatic cancer.

Heavy metals altered the xenobiotic metabolism of rats by targeting the GST enzyme: An in vitro and in silico study

Among all the heavy metals, Pb, Cd, and As are the most harmful pollutants in the environment. They reach into the organisms via various levels of food chains i.e. air and water. Glutathione-s-transferase (GST, E.C. 2.5.1.18), a key enzyme of xenobiotics metabolism, plays an important role in the removal of several toxicants. The present study aimed to evaluate any inhibitory action of these heavy metals on the GST enzyme isolated from the hepatic tissues of rats. A 10 % (w/v) homogenate of rat liver was prepared in cold and centrifuged at 4 °C at 9000xg for 30 min. The supernatant was collected and kept frozen at −20 °C or used fresh for carrying out different experiments. The activity of GST was monitored spectrophotometrically at 340 nm using 220 μg of soluble protein with varying equal substrate concentrations (0.125–2 mM) in phosphate buffer (50 mM, pH 6.5). To assess the impact of heavy metals on the enzyme activity, different concentrations of Cd (0–0.6 mM) and Pb (0–2 mM) were added to the reaction mixture followed by monitoring the residual activity. The optimum temperature and pH of rat liver GST were found to be 37 °C and 6.5, respectively. The Km value for GST was 0.69 mM and the Vmax was found to be 78.67 U/mg. The Cd and Pb significantly altered the kinetic behaviour of the enzyme. The Vmax and Kcat/Km parameters of GST were recorded to be decreased after interaction with Cd and Pb individually and showed a mixed type of inhibition pattern suggesting that these inhibitors may have a greater binding affinity either for the free enzyme or the substrate-enzyme complex. These metals showed a time-dependent enzyme inhibition profile. Cd was found to be the most potent inhibitor when compared to other treated metals; the order of inhibitory effect of metal ions was Cd>Pb>As. The in silico ion docking analysis for determining the probable interactions of Cd and Pb with fragmented GST validated that Cd exhibited higher inhibition potential for the enzyme as compared to Pb. The results of the present study indicated that exposure of both the Cd and Pb may cause significant inhibition of hepatic GST; the former with higher inhibitory potential than the later. However, As proved to be least effective against the enzyme under the aforesaid experimental conditions.

Structural basis for inhibition of the SARS-CoV-2 nsp16 by substrate-based dual site inhibitors.

Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.

Molecular Modeling Studies to Mimic the Binding Hypothesis of NEU3 Sialidase and EGFR in Nonsmall Cell Lung Carcinoma

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic ([Formula: see text]-H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients.

Exploring Radioiodinated Anastrozole and Epirubicin as AKT1-Targeted Radiopharmaceuticals in Breast Cancer: In Silico Analysis and Potential Therapeutic Effect with Functional Nuclear Imagining Implications.

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy

Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.

Growth inhibition of P. aeruginosa by methanol extract of Bridelia stipularis and identification of active components using in silico studies

BackgroundAntimicrobial resistance among pathogens is an emerging problem, gaining significant importance recently. Pharmaceutical scientists are constantly exploring innovative and effective antibacterial agents. Pseudomonas aeruginosa (P. aeruginosa) is a bacterium primarily responsible for pneumonia and infections in the liver, kidneys, and other body parts. It is a Gram-negative bacterium that can be controlled by antibiotics such as ciprofloxacin and levofloxacin. However, this pathogen sometimes exhibits resistance to these antibacterial agents.MethodsRecognizing the well-known potential of plants as sources of medicinal compounds, our study focused on the ethyl acetate, acetone and methanol extract of the leaves of Bridelia stipularis and its impact on the growth of P. aeruginosa using well diffusion method. To gain insight into the composition of the extract, we conducted GC–MS analysis. After identifying the components present in the extract, we assessed the drug-likeness, absorption, distribution, metabolism, and excretion (ADME) and conducted docking studies of the molecules with the selected structural receptors of P. aeruginosa to find out the active component present in the extract.ResultsRemarkably, only methanol extract of Bridelia stipularis demonstrated significant antibacterial activity against this pathogen. In silico investigations revealed that two compounds, namely ethyl iso-allocholate and toluene sulfonylhydrazone derivative, exhibited high inhibition potencies. All structural receptors of the pathogen taken for this study were well inhibited by ethyl iso-allocholate while the receptors such as laconizing lipase and penicillin-binding protein of the bacterium were bound well with the 4-phenyl-3-penten-2-one p-toluene sulfonylhydrazone.ConclusionsObservations of this study clearly establish that the two phytochemicals present in the methanolic extract, i.e., ethyl iso-allocholate and toluene sulfonylhydrazone derivative of Bridelia stipularis leaves are highly active against the growth of the opportunistic pathogen P. aeruginosa.Graphical abstract

Investigation of 2,4-Dihydroxylaryl-Substituted Heterocycles as Inhibitors of the Growth and Development of Biotrophic Fungal Pathogens Associated with the Most Common Cereal Diseases.

Climate change forces agriculture to face the rapidly growing virulence of biotrophic fungal pathogens, which in turn drives researchers to seek new ways of combatting or limiting the spread of diseases caused by the same. While the use of agrochemicals may be the most efficient strategy in this context, it is important to ensure that such chemicals are safe for the natural environment. Heterocyclic compounds have enormous biological potential. A series of heterocyclic scaffolds (1,3,4-thiadiazole, 1,3-thiazole, 1,2,4-triazole, benzothiazine, benzothiadiazine, and quinazoline) containing 2,4-dihydroxylaryl substituents were investigated for their ability to inhibit the growth and development of biotrophic fungal pathogens associated with several important cereal diseases. Of the 33 analysed compounds, 3 were identified as having high inhibitory potential against Blumeria and Puccinia fungi. The conducted research indicated that the analysed compounds can be used to reduce the incidence of fungal diseases in cereals; however, further thorough research is required to investigate their effects on plant-pathogen systems, including molecular studies to determine the exact mechanism of their activity.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Coumarin-based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors.

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits 'drug-like' metabolic stability and half-life in human and mouse liver microsomes and plasma. Compound 3a was employed as a chemical tool to determine pan-AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan-AKR1C inhibitors, 3a demonstrated no radiation sensitization effect in a radiation-resistant prostate cancer cell line model. Pan-AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT-737, daunorubicin or dexamethasone, in two patient-derived T-cell ALL and pre-B-cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT-737 and daunorubicin in the T-cell ALL cell line model. Thus, the inhibitory profile of the AKR1C family inhibitor required to effect enhancement of chemotherapeutic cytotoxicity may be chemotherapeutic agent-specific in leukemia.

Design and radiosynthesis of class-IIa HDAC inhibitor with high molar activity via repositioning the 18F-radiolabel

The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74–1.51 GBq/µmol, 20–41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.

Molecular Modeling of Brassicaceae Derivatives for Inhibiting Lipoxygenases: A Promising Therapeutic Strategy.

Inflammation plays a crucial role in the body's defense mechanisms, but uncontrolled inflammation can lead to chronic and pathological conditions. This study aimed to identify natural compounds as potential replacements for the synthetic drug Zileuton, known for its side effects. Utilizing the MOE and Molegro modeling methods, several molecules were evaluated, and three compounds, namely 1-Isothiocyanatopent-4-en-2-ol, 7-Isothiocyanatohept-1-ene, and 5- (Isothiocyanatomethyl)-1,2,3-trimethoxybenzene, exhibited superior inhibitory properties. These compounds consistently demonstrated low energy values, indicating high inhibition potency. Notably, 5-(Isothiocyanatomethyl)-1,2,3-trimethoxybenzene emerged as the most promising candidate among all tested compounds. These findings provide valuable insights for the development of alternative anti-inflammatory agents. Further research is required to assess the efficacy and safety profiles of these compounds in clinical settings. This study represents a significant advancement in the search for innovative therapeutic strategies to manage inflammation-related disorders.

A top-down approach for studying the in-silico effect of the novel phytocompound tribulusamide B on the inhibition of Nipah virus transmission through targeting fusion glycoprotein and matrix protein

The proteins of Nipah virus ascribe to its lifecycle and are crucial to infections caused by the virus. In the absence of approved therapeutics, these proteins can be considered as drug targets. This study examined the potential of fifty-three (53) natural compounds to inhibit Nipah virus fusion glycoprotein (NiV F) and matrix protein (NiV M) in silico. The molecular docking experiment, supported by the principal component analysis (PCA), showed that out of all the phytochemicals considered, Tribulusamide B had the highest inhibitory potential against the target proteins NiV F and NiV M (-9.21 and −8.66 kcal mol−1, respectively), when compared to the control drug, Ribavirin (-7.01 and −6.52 kcal mol−1, respectively). Furthermore, it was found that Tribulusamide B pharmacophores, namely, hydrogen donors, acceptors, aromatic and hydrophobic groups, contributed towards the effective residual interactions with the target proteins. The molecular dynamic simulation further validated the results of the docking studies and concluded that Tribulusamide B formed a stable complex with the target proteins. The data obtained from MM-PBSA study further explained that the phytochemical could strongly bind with NiV F (-31.26 kJ mol−1) and NiV M (-40.26 kJ mol−1) proteins in comparison with the control drug Ribavirin (-13.12 and −13.94 kJ mol−1, respectively). Finally, the results indicated that Tribulusamide B, a common inhibitor effective against multiple proteins, can be considered a potential therapeutic entity in treating the Nipah virus infection.

Comparative characterisation of an ecto-5'-nucleotidase (CD73) in non-tumoral MCF10-A breast cells and triple-negative MDA-MB-231 breast cancer cells.

Ecto-5'-nucleotidase (CD73) hydrolyses 5'AMP to adenosine and inorganic phosphate. Breast cancer cells (MDA-MB-231) express high CD73 levels, and this enzyme has been found to play a tumour-promoting role in breast cancer. However, no studies have sought to investigate whether CD73 has differential affinity or substrate preferences between noncancerous and cancerous breast cells. In the present study, we aimed to biochemically characterise ecto-5'-nucleotidase in breast cancer cell lines and assess whether its catalytic function and tumour progression are correlated in breast cancer cells. The results showed that compared to nontumoral breast MCF-10A cells, triple-negative breast cancer MDA-MB-231 cells had a higher ecto-5'-nucleotidase expression leveland enzymatic activity. Although ecto-5'-nucleotidase activity in the MDA-MB-231 cell line showed no selectivity among monophosphorylated substrates, 5'AMP was preferred by the MCF-10A cell line. Compared to the MCF-10A cell line, the MDA-MB-231 cell line has better hydrolytic ability, lower substrate affinity, and high inhibitory potential after treatment with a specific CD73 inhibitor α,β‑methylene ADP (APCP). Therefore, we demonstrated that a specific inhibitor of the ecto-5-nucleotidase significantly reduced the migratory and invasive capacity of MDA-MB-231 cells, suggesting that ecto-5-nucleotidase activity might play an important role in metastatic progression.

Nonsymmetrically Substituted 1,1'-Biphenyl-Based Small Molecule Inhibitors of the PD-1/PD-L1 Interaction.

Therapeutic antibodies directed against either programmed cell death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy in the treatment of various cancers. In contrast with antibodies, small molecules have the potential for increased tissue penetration; better pharmacology; and therefore, improved antitumor activity. A series of nonsymmetric C2 inhibitors were synthesized and evaluated for PD-1/PD-L1 interaction inhibition. These compounds induced PD-L1 dimerization and effectively blocked PD-L1/PD-1 interaction in a homogeneous time-resolved fluorescence (HTRF) assay with most inhibitors exhibiting IC50 values in the single-digit nM range and below. Their high inhibitory potency was also demonstrated in a cell-based coculture PD-1 signaling assay where 2 exhibited an EC50 inhibitory activity of 21.8 nM, which approached that of the PD-L1 antibody durvalumab (EC50 = 0.3-1.8 nM). Structural insight into how these inhibitors interact with PD-L1 was gained by using NMR and X-ray cocrystal structure studies. These data support further preclinical evaluation of these compounds as antibody alternatives.