Inhibitor Type Research Articles

Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR.

The treatment of patients with nonsmall cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC50 values in the nanomolar range. Among these, PD18 and PD56 exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC50 values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

The CRISPR/Cas system-mediated function of Hg2+ on urease activity for colorimetric detection of the tumor biomarker in clinical samples

Detecting tumor biomarkers in blood samples is essential in cancer diagnosis and prognosis. This study proposes a CRISPR/Cas system-mediated colorimetric assay to detect the tumor biomarker in human serum samples. It involves using the tumor biomarker as a switch of the CRISPR/Cas system to modulate the function of Hg2+, which is a typical urease inhibitor. The detection of carcinoembryonic antigen (CEA) is demonstrated as an example. The CEA aptamer is used to activate the CRISPR/Cas system, allowing for the cleavage of a single-stranded DNA (ssDNA) rich in thymine (T) nucleotides, thereby causing the inhibition of the urease activity by Hg2+. However, in the presence of CEA, the CRISPR/Cas system cannot be activated due to the specific binding of CEA to its aptamer, which leads to the capture of Hg2+ owing to the formation of a DNA hairpin structure with T-Hg2+-T coordination bonds. Thus, the urease activity is remained. Since the enzymatic hydrolysis of urea by urease increases the pH of the urea solution containing phenol red and changes the solution from yellow to pink, CEA can be detected with the assistance of the colorimetric assay. This method shows high sensitivity and selectivity for CEA with a detection limit of 0.028 ng/mL. In addition, serum samples from patients with normal and abnormal levels are tested to verify the validity of the proposed method for practical applications. Overall, this study provides a simple, fast, and stable colorimetric assay to detect the tumor biomarker in human serum and has great potential for early cancer screening and prognostic determination.

Cardiovascular, Kidney, and Safety Outcomes With GLP-1 Receptor Agonists Alone and in Combination With SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter 2) inhibitors both improve cardiovascular and kidney outcomes in people with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. We searched MEDLINE and Embase databases from inception until July 12, 2024, for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance-weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50% reduction in estimated glomerular filtration rate, kidney failure or death caused by kidney failure, and annualized rate of decline in estimated glomerular filtration rate (estimated glomerular filtration rate slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024565765). We identified 3 trials with 1743 of 17 072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (hazard ratio [HR], 0.79 [95% CI, 0.71-0.87]), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77 [95% CI, 0.54-1.09] and HR, 0.79 [95% CI, 0.71-0.87], respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR, 0.58 [95% CI, 0.36-0.93] and HR, 0.73 [95% CI, 0.63-0.85]; P-heterogeneity=0.26). Effects on the composite kidney outcome (risk ratio, 0.79 [95% CI, 0.66-0.95]) and estimated glomerular filtration rate slope (0.78 mL/min/1.73 m2/y [95% CI, 0.57-0.98]) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). In people with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

Enhanced renoprotective effects of combined glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: Real-world evidence.

Developing a more effective treatment for the global impact of diabetic kidney disease is crucial. This study examined the renoprotective effects of combining glucagon-like peptide-1 receptor agonists (GLP-1 RA) with sodium-glucose cotransporter 2 inhibitors (SGLT2i) compared to SGLT2is alone in type 2 diabetes (DM). This retrospective cohort study used data from the TriNetX Global Collaborative Network. Type 2 DM patients with estimated glomerular filtration rates ≥60 mL/min/1.73 m2 who used GLP-1 RA or SGLT2i between January 1, 2013, and December 31, 2023. Propensity score matching balanced baseline characteristics, resulting in 71,186 patients in each group (combined GLP-1 RA and SGLT2i therapy vs SGLT2i alone). Cox regression model was adopted to compare outcomes over a 5-year period, including major adverse kidney events (MAKE), acute kidney injury (AKI), end-stage kidney disease (ESKD), and all-cause mortality. After matching, the average age was 57.1 ± 10.8 years for the GLP-1 RA plus SGLT2i group and 57.2 ± 11.7 years for the SGLT2i-only group. The GLP-1 RA plus SGLT2i group had significantly lower risk of MAKE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.69-0.77), AKI (HR: 0.82, 95% C0I: 0.77-0.87), ESKD (HR: 0.61, 95% CI: 0.47-0.78), and all-cause mortality (HR: 0.54, 95% CI: 0.50-0.58) compared to the SGLT2i-only group. Moreover, subgroup analyses showed consistent benefits across different subgroups. Dual therapy with GLP-1 RA and SGLT2i is supported to enhance renal outcomes and address the growing burden of diabetic kidney disease.

Enhancing Antibacterial Efficacy: Combining Novel Bacterial Topoisomerase Inhibitors with Efflux Pump Inhibitors and Other Agents Against Gram-Negative Bacteria.

The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs' minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections.

Effect of tadalafil on pulmonary hypoplasia in congenital diaphragmatic hernia of rat fetuses

Background. Pulmonary hypoplasia and persistent pulmonary hypertension in congenital diaphragmatic hernia are the cause of adverse perinatal outcomes. Dissatisfaction with the outcomes of intrauterine surgical correction of CDH determines the search for alternative non-surgical prenatal methods of treating pulmonary hypoplasia in CDH. Objective. To study the effect of a reversible selective inhibitor of specific phosphodiesterase type 5 (tadalafil) on the development of fetal lungs in rats in a model of congenital diaphragmatic hernia. Design and methods. An experimental study was conducted on the possibility of correcting fetal lung hypoplasia in rats when modeling a diaphragmatic hernia with nitrophen (100 mg orally, once on the 9th day of pregnancy). Results. Congenital diaphragmatic hernia was recorded in 12.5 % of offspring. Subcutaneous administration of tadalafil to pregnant rats (0,83 mg/kg, for 10 days, from the 9th day of pregnancy) in the lungs of fetuses increases the number of alveoli (by 22 % at p ≤ 0.05), the area of microvasculature vessels and the volume of lung parenchyma increases (by 1.25 % and 1.13 % more (at p ≤ 0.05)). Conclusion. The results obtained from the first experiment conducted in the Russian Federation to study the effect of tadalafil on the lungs in congenital diaphragmatic hernia of the fetus are comparable with the data of the authors who used sildenafil, however, the use of tadalafil seems more optimal due to the ease of its administration for potential practical use.

Unexpected inhibition roles of methane nanobubbles on hydrate decomposition

Uncontrolled hydrate decomposition poses extraordinary risks, such as submarine landslides during hydrate exploitation, and gas leakage during hydrate storage/transportation. Previous studies suggested inhibitors can effectively prevent hydrate decomposition by adsorbing onto the hydrate surface. However, herein, we find inhibitors have very limited adsorption coverages on hydrate, which cannot fully explain their good performance. In this study, by combining experiments and molecular simulations, a new inhibition mechanism is proposed, in which nanobubbles act as the primary factor in inhibiting hydrate decomposition. Specifically, when PVP (a typical inhibitor) is added into the solution, its hydrophobic groups interact strongly with CH4, thereby increasing CH4 solubility and inducing the formation of CH4 nanobubbles. These nanobubbles are then encapsulated within the hydrate and inhibit hydrate decomposition by the following process: nanobubbles gradually become exposed to the aqueous phase during hydrate decomposition and release CH4 to the region near the nanobubble-hydrate interface. The high local CH4 concentrations near the nanobubble-hydrate interface would promote the formation of microstructures necessary for hydrate nucleation, thereby amplifying the driving force toward nucleation and consequently inhibiting hydrate decomposition. Our proposed “nanobubble inhibition mechanism” can provide a theoretical foundation for developing and applying inhibitors to prevent hydrate decomposition in various industrial applications.

Effects of Dapagliflozin on myocardial performance in non-diabetic patients with Heart failure with reduced and mid-range ejection fraction (DAPA ECHO trial)

Abstract Background Sodium-glucose cotransporter type-2 inhibitors (SGLT2i) showed to reduced morbidity andmortality in HF patients. The aim of this study was to assess potential effects of dapagliflozin in non-diabetic patients with heart failure (HF) with reduced and mildly reduced ejection fraction (HFrEF and HFmrEF) on cardiac function assessed by speckle tracking echocardiography (STE). Methods This randomized, prospective, single-center, open-label trial compared consecutive non-diabetic outpatients with HFrEF or HFmrEF receiving dapagliflozin with patients treated with optimal medical therapy (OMT) except SGLT2i (Fig.1). Primary endpoint was the modification of left ventricular (LV) global longitudinal strain (GLS), diastolic function (as peak atrial longitudinal strain, PALS) and right ventricular (RV) function by STE from baseline to 6 months. Cardiovascular events and parameters of congestion were assessed as safety-exploratory endpoints. Results Overall, 88 patients (38% HFmrEF) were enrolled and randomized to start dapagliflozin on top of OMT (n=44) or to continue with OMT (n=44). All STE values improved in dapagliflozin group after 6 months, while there was a non-significant improvement in OMT group (Fig.1). Moreover, when comparing the modification of STE parameters at follow up in HFrEF and HFmrEF patients, only the main treatment effect resulted statistically significant in both groups (p<0.0001), indicating a significant difference between dapagliflozin and OMT. Conclusions This study provided randomized data on the beneficial effect of dapagliflozin in non-diabetic patients with HFrEF and HFmrEF in terms of myocardial performance measured by the most sensitive echocardiographic technique i.e. STE. This suggests its usefulness for LV reverse remodeling and better quality of life in patients with HFrEF and HFmrEF.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients.

We comment on an article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and their impact on comorbidities. SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys, lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine. Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control. In addition, SGLT2i has been shown to be effective in anti-apoptosis, weight loss, and cardiovascular protection. Accordingly, it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Improving docking and virtual screening performance using AlphaFold2 multi-state modeling for kinases

Structure-based virtual screening (SBVS) is a crucial computational approach in drug discovery, but its performance is sensitive to structural variations. Kinases, which are major drug targets, exemplify this challenge due to active site conformational changes caused by different inhibitor types. Most experimentally determined kinase structures have the DFGin state, potentially biasing SBVS towards type I inhibitors and limiting the discovery of diverse scaffolds. We introduce a multi-state modeling (MSM) protocol for AlphaFold2 (AF2) kinase structures using state-specific templates to address these challenges. Our comprehensive benchmarks evaluate predicted model qualities, binding pose prediction accuracy, and hit compound identification through ensemble SBVS. Results demonstrate that MSM models exhibit comparable or improved structural accuracy compared to standard AF2 models, enhancing pose prediction accuracy and effectively capturing kinase-ligand interactions. In virtual screening experiments, our MSM approach consistently outperforms standard AF2 and AF3 modeling, particularly in identifying diverse hit compounds. This study highlights the potential of MSM in broadening kinase inhibitor discovery by facilitating the identification of chemically diverse inhibitors, offering a promising solution to the structural bias problem in kinase-targeted drug discovery.

Sodium-glucose cotransporter 2 inhibitors and cardiovascular events among patients with type 2 diabetes and low-to-normal body mass index: a nationwide cohort study

BackgroundPatients with low-to-normal body mass index (BMI; < 25.0 kg/m2) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials.MethodsThis cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0–22.4, 22.5–24.9, 25.0–29.9, 30.0–34.9, and 35.0 ≤ kg/m2). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category.ResultsAmong participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m2, 1.9% [n = 5,350]; 20.0–22.4 kg/m2, 8.5% [n = 23,818]; and 22.5–24.9 kg/m2, 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m2, HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0–22.4 kg/m2, HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5–24.9 kg/m2, HR [95%CI] = 0.92 [0.84 to 1.01]).ConclusionsThe protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors.Graphical abstract

Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case–control study

BackgroundNon-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive.MethodsA nested case–control study was conducted using Taiwan’s National Health Insurance Research Database for 2011–2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual’s age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed.ResultsThere were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46–1.52] and 0.85 [0.63–1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38–0.97]).ConclusionGLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Possible mechanism of effect of the empagliflozin on cardiovascular mortality

Introduction. The development of heart failure is closely associated with the appearance of life threatening arrhythmias, which are often a terminal event for these patients. An analysis of randomized clinical trials of inhibitors of sodium-glucose cotransporter type 2 indicates the clinically significant potential of these drugs as agents with antiarrhythmic properties. However, at the moment the full mechanism by which this effect can be realized is still not fully understood.Aim. To evaluate the effect of empagliflozin on the transmembrane calcium currents and the intracellular calcium transients on isolated ventricular cardiomyocytes of mice under conditions of normoglycemia.Materials and methods. In the experiment, ventricular cardiomyocytes were isolated from 12 outbred male mice. 2 groups were formed: group № 1 – control ventricular cardiomyocytes; group № 2 – ventricular cardiomyocytes after two hours incubation with 5 µmol/L empagliflozin solution. Transmembrane calcium currents were recorded and intracellular calcium transients were assessed.Results and discussion. Incubation of ventricular cardiomyocytes with empagliflozin significantly increased ICa current density and accelerated Ca2+ temporal dynamics. The amplitude of the Ca2+ wave and the rate of rise and decay were increased and the duration of the Ca2+ wave was shortened.Conclusion. The result of the experiment indicates that empagliflozin is able to modulate Ca2+-dependent mechanism of the excitation-contraction-coupling, enhancing and accelerating Ca2+ release into cytoplasm and reuptake. This presumably can optimize, namely reduce the time of systole and enhance it, which may be one of the important elements in the manifestation of empagliflozin antiarrhythmic properties.

Sodium-Glucose Co-transporter-2 Inhibitors in Type 1 Diabetes Mellitus: The Framework for Recommendations for Their Potential Use.

The growing prevalence of overweight/obesity, the persistence of inadequate glycemic control among themajority of affected individuals, and thestill unacceptably high risk of cardiovascular morbidity and mortality among population with type 1 diabetes mellitus (T1D), impose an urgent need for theintroduction of non-insulin glucose-lowering agents in the therapeutic armamentarium. Given thattheir antihyperglycemic mechanism of action is independent of endogenous insulin secretion and thatthe observed cardio-renal benefits are unrelated to their glucose-lowering properties, one can speculate that the use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) could provide benefits in T1D, similar to the ones observed among individuals with type 2 diabetes mellitus, chronic kidney disease (CKD), and heart failure. Available evidence from randomized controlled trials suggests that treatment with SGLT2is as adjunct to insulin in T1D results in modest reductions in glycated hemoglobin and body weight. Additionally, SGLT2is ameliorate albuminuria, and thus delay or prevent thedevelopment of CKD inT1D. However, use of SGLT2is is associated with an increased risk of diabetic ketoacidosis (DKA) in T1D. This commentary aims at providing a framework for practical recommendations regarding the potential use of SGLT2is in adults with T1D, based on the individual's risk level for DKA development, the presence of inadequate glycemic control and related cardio-renal complications.

Computational exploration of naturally derived peptides inhibitory mechanisms against ACE enzyme, from interactions to structural-dynamics

Naturally derived peptides have gained significant attention because of their potential to reduce blood pressure. These peptides can be derived from various sources, including snake venom, marine organisms, cow's milk, seahorses, and plants. Investigating the underlying mechanisms of these peptides in lowering blood pressure is crucial for replacing synthetic drugs currently in use. In this regard, we conducted in silico studies, such as molecular docking, classical molecular dynamics (MD) simulations, and QM/MM simulation methods, on two naturally derived peptides (PAGPRGPA and WALKGYK) and Angiotensin II (ANGII) as the enzyme substrates for binding to sACE. The results of 500 ns MD calculations showed that the WALKGYK peptide occupies the ACE binding site, similar to the ANGII and BPPb peptides, two distinguished C-domain-specific inhibitors. Furthermore, QM/MM calculations demonstrated that no peptide bond cleavage was mediated by Zn2+ at the catalytic site of the peptides. However, during the 500 ns MD simulation, the backbone oxygens of LYS4 and GLY5 of the WALKGYK peptides were tightly coordinated to the Zn2+ ion. Free energy calculations also confirmed the higher affinity of the WALKGYK peptides for binding to sACE. In addition, structural analysis correlation showed a different pattern in PAGPRGPA compared to WALKGYK and ANGII. Despite the similarity of the peptide PAGPRGPA to typical ACE peptide inhibitors with hydrophobic ends, the electrostatic composition of the WALKGYK peptide showed a higher tendency towards ACE inhibition. Therefore, peptide residue compositions, such as WALKGYK, can be considered for designing new inhibitors with fewer side effects for sACE C-terminal inhibitors.

Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood-Brain Barrier Transport of Mesoridazine and Metoclopramide.

Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with Km values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H+-coupled organic cation (H+/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H+/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.

Mitigation effect of a biodegradable surfactant N,N,N-trimethyl-2-(((hexadecyloxy)carbonyl)oxy)ethan-1-aminiumiodide for mild steel corrosion in 5% HCl: Experimental and theoretical insights

A cleavable cationic surfactant having carbonate linkage, N,N,N-trimethyl-2-(((hexadecyloxy)carbonyl)oxy)ethan-1-aminiumiodide referred to as THC was synthesised and characterized employing elemental analysis, FT-IR (Fourier Transform Infrared Spectroscopy), 1H NMR (Nuclear Magnetic Resonance) and 13C NMR. The extent of corrosion inhibition of THC was for the first time studied experimentally and theoretically on mild steel (MS) substrate in 5 % HCl solution at temperatures 303, 313, 323, 333, 343, 353 K. Experimental investigations include gravimetric analysis, potentiodynamic polarization (PDP) and electrochemical impedance analysis (EIS). THC provided maximum inhibition efficiency of 93.2 % at concentration of 1×10−4 M at 303 K which was further raised to 98.1 % at 353 K. PDP studies reveal that given surfactant is mixed type inhibitor. Surface studies such as contact angle measurement, AFM (Atomic Force Microscopy), SEM-EDX (Scanning Electron Microscope-Energy Dispersive X-ray Analysis), and XPS (X-ray Photoelectron Spectroscopy) were employed to justify the adsorption of inhibitor molecules on MS surface. Furthermore, biodegradability test on THC was done to support the environment friendly nature of the surfactant.

Exploring the performance of Coriandrum sativum extract as an effective corrosion inhibitor for mild steel in a [formula omitted] medium, and its sustainable application in the eco-friendly removal of heavy metals

This research investigated the performance of coriander seeds, for the first time, in two critical phenomena: wastewater treatment and corrosion inhibition in acidic environments. On one hand, the aqueous extracts from Coriandrum sativum seeds (CE) were evaluated for mild steel corrosion inhibition in a 2.0 M phosphoric acid medium using several techniques such as phytochemical analysis (GC-MS), potentiodynamic polarization, electrochemical impedance spectroscopy, scanning electron microscopy (SEM-EDAX) and theoretical analyses, including DFT calculations and Molecular Dynamic Simulations, further elucidated the major chemical components. First, the phytochemical analysis has proved that CE contains heteroatoms. Second, the electrochemical results indicate that CE behaves as a mixed type inhibitor and the corrosion reaction is controlled by charge transfer process. Finally, The theoretical calculations confirmed that the active compounds of CE can be adsorbed on the Fe (1 1 0) surface through physical patterns and by sharing charges with iron to form coordinate bonds. The acquired results have shown a strong correlation between corrosion inhibition efficiency that was about 93 %, SEM-EDAX and DFT parameters. On the other hand, the study examined coriander seeds (CS) in powder form as a removal of copper ions in aqueous solutions through Atomic Absorption Spectroscopy and Inductively Coupled Plasma analysis. The parametric study was effectuated by establishing the effect of contact time, adsorbent mass, solution pH and stirring speed. The removal rate was about 79 %. Regeneration studies showed that CS could be reused for five cycles without significant loss of effectiveness. SEM-EDAX analysis has proved the studied process.

Onametostat, a PfPRMT5 inhibitor, exhibits antimalarial activity to Plasmodium falciparum.

Protein arginine methyltransferases (PRMTs) play critical roles in Plasmodium falciparum, a protozoan causing the deadliest form of malaria, making them potential targets for novel antimalarial drugs. Here, we screened 11 novel PRMT inhibitors against P. falciparum asexual growth and found that onametostat, an inhibitor for type II PRMTs, exhibited strong antimalarial activity with a half-maximal inhibitory concentration (IC50) value of 1.69 ± 0.04 µM. In vitro methyltransferase activities of purified PfPRMT5 were inhibited by onametostat, and a shift of IC50 to onametostat was found in the PfPRTM5 disruptant parasite line, indicating that PfPRTM5 is the primary target of onametostat. Consistent with the function of PfPRMT5 in mediating symmetric dimethylation of histone H3R2 (H3R2me2s) and in regulating invasion-related genes, onametostat treatment led to the reduction of H3R2me2s level in P. falciparum and caused the defects on the parasite's invasion of red blood cells. This study provides a starting point for identifying specific PRMT inhibitors with the potential to serve as novel antimalarial drugs.

Synergistic inhibition effect of diolefinic dye and silver nanoparticles for carbon steel corrosion in hydrochloric acid solution

The current work looks at the inhibitory effects of a diolefinic dye, namely 1,4-bis((E)-2-(3-methyl-2,3-dihydrobenzo[d]thiazol-2-yl) vinyl) benzene iodide salt, in relation to CS corrosion mitigation in hydrochloric acid (HCl) environment. This study uses a variety of experimental methodologies, including weight loss (WL) analysis, electrochemical tests, and theoretical considerations. The synergistic effect of diolefinic dye and AgNPs on the corrosion inhibition of CS in 1 M HCl was investigated. The inhibition efficiency (IE) displays a notable enhancement as the concentration of the dye is elevated and as the temperature raises the IE increases. The diolefinic dye exhibited % IE of 83% even at low concentration (1 × 10–4 M) whereas 90% in the presence of (2.26 × 10–10) AgNPs. Tafel graphs demonstrate that the dye follows a mixed type inhibitor. The adsorption of the dye on CS surface follows Langmuir model. Moreover, the influence of temperature and the activation parameters disclose that diolefinic dye is chemisorbed on the CS surface. The synergistic coefficient of the diolefinic dye and AgNPs under various concentration conditions was greater than unity. The surface morphology of CS sheets was confirmed by scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX). Density Functional Theory (DFT) calculations provide theoretical support for the inhibitory effects of the examined dye. Notably, there is a high agreement between the findings of practical studies and theoretical expectations.