Inhibitor Activity Research Articles

Facile Synthesis of N-(4-Bromo-3-methylphenyl)pyrazine-2-carboxamide Derivatives, Their Antibacterial Activities against Clinically Isolated XDR S. Typhi, Alkaline Phosphatase Inhibitor Activities, and Docking Studies.

The emergence of extensively drug-resistant Salmonella Typhi (XDR-S. Typhi) poses a grave public health threat due to its resistance to fluoroquinolones and third-generation cephalosporins. This resistance significantly complicates treatment options, underscoring the urgent need for new therapeutic strategies. In this study, we synthesized pyrazine carboxamides (3, 5a-5d) in good yields through the Suzuki reaction. Afterward, we evaluate their antibacterial activities against XDR-S. Typhi via the agar well diffusion method; 5d has the strongest antibacterial activity with MIC 6.25 (mg/mL). Moreover, in vitro Alkaline Phosphatase inhibitor activity was also determined; 5d is the most potent compound, with an IC50 of 1.469 ± 0.02 µM. Further, in silico studies were performed to find the type of interactions between synthesized compounds and target proteins.

Comparative efficacy of amino acid availability and peptidomic analysis of alternative proteins from different sources under dynamic in vitro protein digestion

The increasing global demand for animal protein highlights the critical necessity of exploring alternative protein sources. Accessing the nutritional characteristics of emerging alternative proteins is vital for food processing and consumer acceptance. This study investigated the amino acid availability and peptidomics profiles of plant- (soy), fungal- (filamentous fungus Fusarium venenatum), microalgae- (Nannochloropsis oculata), and insect-based (black soldier fly) proteins using an advanced dynamic in vitro digestion system, with whey protein as a reference. After gastric digestion, soy and mycelial proteins, despite displaying distinct microstructures, exhibited slightly higher protein digestibility levels of 28.79% and 26.36%, respectively, compared to whey protein (22.39%). However, following small intestinal digestion, whey protein (61.31%) significantly outperformed alternative proteins. Mycelial protein (43.71%) exhibited digestibility similar to soy protein (46.12%), markedly surpassing both microalgae protein (33.35%) and insect protein (26.58%). Notably, insect protein achieved an amino acid availability nearly approaching that of whey protein, underscoring its substantial proteolysis capability. Furthermore, microalgae protein produced the highest percentage and number of bioactive peptides under simulated digestion, suggesting potential health benefits such as angiotensin I-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) inhibitor activities, which could mitigate the risk of hypertension and Type 2 diabetes. Alternative proteins from different sources demonstrate diverse digestive mechanisms and proteolysis profiles, thereby bolstering their potential applications as nutritious food ingredients in the future.

Comparison of rice bran characteristics fermented by mono- or di-strain probiotics based on omics technology

Rice bran is a premium agricultural byproduct rich in nutrients and bioactive substances. The aim of this study was to compare the effects of fermentation with Bacillus subtilis, Lactobacillus plantarum, and a mixture of both on the bacterial communities and metabolic functions of rice bran based on omics techniques. The results showed that probiotic fermentation decreased crude fiber (CF) content, phytic acid, and trypsin inhibitor activity (TIA), and increased trichloroacetic acid soluble protein (TCA-SP), reducing sugar (RS), and total phenol (TP) in rice bran. Ten dominant genera with relative abundances greater than 1% were successfully identified, and probiotic fermentation significantly reduced the relative abundances of Enterobacter, Kasakonia, and Pantoea. A total of 63 differentially expressed metabolites (DEMs) were identified and further analysis revealed that probiotic fermentation increased essential amino acids, phenolic compounds, and organic acids in rice bran. Additionally, the di-strain probiotic fermentation of Bacillus subtilis and Lactobacillus plantarum facilitated the growth of beneficial microbiota (Limosilactobacillus, Prevotella and Dialister) and the production of bioactive substances (lactic acid, catechol, beta-tyrosine, etc.). In conclusion, co-fermentation of di-strain probiotics is a valuable method to produce functional compounds and enhance the health-promoting properties of rice bran.

Evaluation of α-glucosidase inhibitor activity and bioactive compounds in purple wheat flour yogurts

Nowadays, the food industry attaches more importance to studies on using purple components in food formulations due to their bioactive properties. This study evaluated the phenolic compound content, antioxidant activity, physicochemical properties, sensory properties, and α-glucosidase activities in yogurt enriched with purple wheat flour. Yogurts were produced using varying concentrations of purple wheat flour labeled as sample A (1.5 %), sample B (3 %), and sample C (4.5 %). It was observed that incorporating purple wheat flour led to a decrease in pH and an increase in L*, a*, and b* values, as well as the acidity and viscosity of the yogurts. Sample C contained the highest phenolic content (37.6 mg GAE/100 g dry matter) on day 14, along with the highest flavonoid content (14.59 mg CE/100 g) on day 21 when than control yogurt. In addition, sample C had the highest α-glucosidase activity (38.35 %) on day 14 and anthocyanin content (13.55 g/100 g) on day 21. As a result, C yogurt can be consumed as a diabetic product with antidiabetic and antihypertensive properties by reaching optimal α-glycosidase inhibition activity. Furthermore, yogurts containing purple wheat flour received higher sensory scores from panelists.

Abstract C025: A novel pan-RAS/β-catenin inhibitor, ADT-030, produces tumor regression in PDX models of pancreatic cancer

Abstract BACKGROUND: The absence of symptoms often leads to late diagnosis of pancreatic ductal adenocarcinoma (PDAC) limiting treatment options. Tumor cell proliferation and invasion/metastasis are usually driven by KRAS mutations and activation of Wnt/β-catenin pathway components. The recent approval of KRASG12C-specific inhibitors for lung cancer has validated RAS as a druggable target but has had limited application for PDAC given the rarity of this codon in PDAC. In addition, no Wnt/β-catenin inhibitors have been FDA approved. Thus, drugs which inhibit these important targets are urgently needed for PDAC and other cancers. Here, we describe treatment results with ADT-030, a novel dual pan-RAS/β-catenin inhibitor in murine models of PDAC and lung cancer. METHODS: In vitro assays of growth inhibition, colony formation, apoptosis, and cell cycle, along with western blotting for RAS signaling were performed to assess potency and selectivity of ADT-030. Murine 2838c3-Luc KRASG12D PDAC cells were implanted orthotopically into the pancreas of C57BL/6J mice and cells from two PDAC patient-derived xenograft (PDX) models harboring KRASG12D or KRASG12C mutations were implanted subcutaneously (SC) in NSG mice to evaluate the antitumor activity of ADT-030. ADT-030 was administered once daily by gavage 5x/week for 4 weeks. RESULTS: ADT-030 potently inhibited the growth of PDAC cells in vitro harboring the most prevalent KRASG12D mutation as well as those with KRASG12C. Annexin V assay revealed the capacity of ADT-030 to trigger apoptosis in KRAS mutant cells with minimal impact on BxPC3 RASWT cells. Cell cycle analysis using propidium iodide staining revealed that ADT-030 arrested cells in the G2/M phase. Other experiments showed that ADT-030 simultaneously suppressed both MAPK/AKT signaling and β-catenin transcriptional by inhibiting PDE10 and activating cGMP/PKG signaling. ADT-030 caused tumor regression in SC PDAC PDX mouse tumor models harboring either KRASG12D or KRASG12C mutations without discernable toxicity. Inhibition of orthotopic PDAC tumor growth by ADT-030 was dose-dependent, causing up to 80% reduction in tumor volume following a 4-week treatment period. In addition, ADT-030 significantly extended survival and yielded a high percentage of cures after stopping treatment in a murine model of KRAS- mutant lung cancer. CONCLUSION: ADT-030, novel dual pan-RAS/β-catenin inhibitor, showed strong and durable antitumor activity in clinically relevant and aggressive murine models of PDAC and lung cancer. ADT-030 is a promising development candidate for treatment of PDAC and other RAS-driven cancers, particularly given the complex KRAS mutation landscape of many cancers. Citation Format: Dhana Sekhar Reddy Bandi, Ganji P Nagaraju, Jeremy B Foote, Adam B Keeton, Xi Chen, Kristy L Berry, Yulia Y Maxuitenko, Upender Manne, Donald J Buchsbaum, Gary A Piazza, Bassel F El-Rayes. A novel pan-RAS/β-catenin inhibitor, ADT-030, produces tumor regression in PDX models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C025.

Abstract IA-05: Targeting KRAS for pancreatic cancer treatment

Abstract The approval of clinically effective inhibitors for KRAS G12C mutant non-small cell lung cancers in 2021 and 2022 marks a significant milestone in anti-KRAS oncogene drug discovery. This success has fueled intense efforts to develop inhibitors targeting additional KRAS mutations. However, primary and treatment-associated acquired resistance limit the depth and duration of efficacy of KRAS G12C selective and likely other KRAS inhibitors. Thus, a major challenge moving forward will be the elucidation of mechanisms of resistance to then guide development of effective combination anti-KRAS therapies. Recent studies have begun to identify mechanisms of acquired resistance, where most involve alterations in components in the RAS signaling network that then cause reactivation of KRAS effector signaling that bypass drug activity. Our studies have established the critical role of reactivation of the RAF-MEK-ERK mitogen activated protein kinase cascade, and the ERK target MYC, in driving resistance in KRAS-mutant pancreatic cancer. To fully understand how aberrant ERK and MYC activation overcomes KRAS inhibitor response, we have established a comprehensive molecular portrait of ERK- and MYC-dependent activities. We have also identified YAP/TAZ-TEAD activation as a mechanism of acquired resistance and have characterized KEAP1 loss as a mechanism of primary resistance. Together, these studies have identified drug combination strategies that enhance KRAS inhibitor activity. Progress in these and other studies will be presented. Citation Format: Channing J. Der. Targeting KRAS for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-05.

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors.

Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α1-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin-Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4.

Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.

Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.

Efficacy of PARP inhibitors in advanced high-grade serous ovarian cancer according to BRCA domain mutations and mutation type.

Preclinical studies have emphasized the potential connection between BRCA specific domains defects and the activity of Poly ADP-ribose polymerase inhibitors (PARPi). Nevertheless, real-world evidence regarding the impact of BRCA domain defects and mutations on PARPi efficacy are limited. The aim of his study was to evaluate the efficacy of PARPi in terms of progression free survival (PFS) according to BRCA domains defects and mutation types. A retrospective analysis was performed among 79 BRCA mutated patients, diagnosed with advanced High-grade serous ovarian carcinoma (HGSOC) who received first- and second-line platinum- based chemotherapy followed by PARPi maintenance treatment. PFS was evaluated according to BRCA1 [Really Interesting Gene (RING), DNA Binding (DBD), Serine Cluster (SCD), BRCA1 C-terminal (BRCT)] and BRCA2 [RAD-51 Domain (RAD-51 BD), DBD] specific domain defects and mutation types [missense (MS), nonsense (NS), frameshift (FS), splicing (S), or large rearrangements (LR)]. After a median follow-up of 51 months, no significant difference in PFS was observed between the BRCA functional domains or mutation types in the BRCA1 and BRCA2 subgroups. Patients with BRCA2 DBD and RAD51-BD defects had the longest (39.8 months) and shortest (24.1 months) median PFS, respectively (p = 0.11). Additionally, patients with BRCA1 DBD defects had the greatest benefit (median PFS = 33.8 months) while those with BRCA1 RING domain mutations experienced the worst outcome (median PFS = 30.9 months (p = 0.43). The efficacy of maintenance treatment with PARPi is independent by BRCA domain defects or mutation types. Patients DBD domain defects experienced numerically longer median PFS compared to those with other BRCA1/2 alterations.

Exploring the Effects of Chirality of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl]imidazolidine-2,4-dione and its Derivatives on the Oncological Target Tankyrase 2. Atomistic Insights.

Tankyrases (TNKS) are homomultimers existing in two forms, viz. TNKS1 and TNKS2. TNKS2 plays a pivotal role in carcinogenesis by activating the Wnt//β-catenin pathway. TNKS2 has been identified as a suitable target in oncology due to its crucial role in mediating tumour progression. The discovery of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl] imidazolidine-2,4-dione, a hydantoin phenylquinazolinone derivative which exists as a racemic mixture and in its pure enantiomer forms, has reportedly exhibited inhibitory potency towards TNKS2. However, the molecular events surrounding its chirality towards TNKS2 remain unresolved. Herein, we employed in silico methods such as molecular dynamics simulation coupled with binding free energy estimations to explore the mechanistic activity of the racemic inhibitor and its enantiomer forms on TNK2 at a molecular level Results: Favourable binding free energies were noted for all three ligands propelled by electrostatic and van der Waals forces. The positive enantiomer demonstrated the highest total binding free energy (-38.15 kcal/mol), exhibiting a more potent binding affinity to TNKS2. Amino acids PHE1035, ALA1038, and HIS1048; PHE1035, HIS1048 and ILE1039; and TYR1060, SER1033 and ILE1059 were identified as key drivers of TNKS2 inhibition for all three inhibitors, characterized by the contribution of highest residual energies and the formation of crucial high-affinity interactions with the bound inhibitors. Further assessment of chirality by the inhibitors revealed a stabilizing effect of the complex systems of all three inhibitors on the TNKS2 structure. Concerning flexibility and mobility, the racemic inhibitor and negative enantiomer revealed a more rigid structure when bound to TNKS2, which could potentiate biological activity interference. The positive enantiomer, however, displayed much more elasticity and flexibility when bound to TNKS2. Overall, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl] imidazolidine-2,4-dione and its derivatives showed their inhibitory prowess when bound to the TNKS2 target via in silico assessment. Thus, results from this study offer insight into chirality and the possibility of adjustments of the enantiomer ratio to promote greater inhibitory results. These results could also offer insight into lead optimization to enhance inhibitory effects.

Plasma proteomes of acute myeloid leukemia patients treated with transfusions reveal signatures of inflammation and hemostatic dysregulation

BackgroundBone marrow aplasia is a common feature in acute myeloid leukemia (AML) patients during their remission induction treatment, and is associated with potential complications such as bleeding, infection and anemia. Frequent platelet and red cell transfusions are administered to prevent and treat these complications. However, platelet counts are poorly associated with bleeding events in this population. Therefore, plasma protein levels could add valuable insights to improve our understanding of the patient's health state. In this study, we aimed to delineate the plasma proteome, including inflammatory pathways, hemostatic and immune components, of AML patients during treatment with intensive transfusion support.MethodsWe employed unbiased mass spectrometry (MS)-based proteomics on longitudinal plasma samples from 10 AML patients during intensive-transfusion treatment phase with healthy individuals as baseline control.ResultsA total of 450 proteins were quantified in plasma samples from AML patients and healthy controls. Alteration in proteins levels were mainly observed for proteins involved in inflammation (e.g. SAA1 and CRP), and complement (e.g. C9 and MASP2) when comparing AML versus healthy individuals. Correlation analysis revealed additional affected protein dynamics, including proteins associated with coagulation cascade, endopeptidase inhibitors activity and lipoprotein remodeling.ConclusionThe plasma proteome from AML patients during intensive treatment shows a disbalance in inflammation, endopeptidase inhibitors activity, lipoprotein remodeling, coagulation and complement. These effects and potential associations with bleeding risk will be further studied in a bigger cohort.

Novel Celecoxib Derivative, RF26, Blocks Colon Cancer Cell Growth by Inhibiting PDE5, Activating cGMP/PKG Signaling, and Suppressing β-catenin-dependent Transcription.

Previous studies have reported that the cGMP-specific PDE5 isozyme is overexpressed in colon adenomas and adenocarcinomas and essential for colon cancer cell proliferation, while PDE5 selective inhibitors (e.g., sildenafil) have been reported to have cancer chemopreventive activity. This study aimed to determine the anticancer activity of a novel PDE5 inhibitor, RF26, using colorectal cancer (CRC) cells and the role of PDE5 in CRC tumor growth in vivo. The objective of this study was to characterize the anticancer activity of a novel celecoxib derivative, RF26, in CRC cells previously reported to lack COX-2 inhibition but have potent PDE5 inhibitory activity. Anticancer activity of RF26 was studied using human CRC cell lines. Its effects on intracellular cGMP levels, cGMP-dependent protein kinase (PKG) activity, β-catenin levels, TCF/LEF transcriptional activity, cell cycle distribution, and apoptosis were measured. CRISPR/cas9 PDE5 knockout techniques were used to determine if PDE5 mediates the anticancer activity of RF26 and validate PDE5 as a cancer target. RF26 was appreciably more potent than celecoxib and sildenafil to suppress CRC cell growth and was effective at concentrations that increased intracellular cGMP levels and activated PKG signaling. RF26 suppressed β-catenin levels and TCF/LEF transcriptional activity and induced G1 cell cycle arrest and apoptosis within the same concentration range. CRISPR/cas9 PDE5 knockout CRC cells displayed reduced sensitivity to RF26, proliferated slower than parental cells, and failed to establish tumors in mice. Further evaluation of RF26 for the prevention or treatment of cancer and studying the role of PDE5 in tumorigenesis are warranted.

Developments of Fms-like Tyrosine Kinase 3 Inhibitors as Anticancer Agents for AML Treatment.

FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

Activity of Fluoroquinolones and Proton Pump Inhibitors against Resistant Oral Bacterial Biofilms, in silico and in vitro Analysis.

Oral bacterial infections are a great health concern worldwide especially in diabetic patients. Emergence of antimicrobial resistance with reference to biofilms in oral cavity is of great concern. We investigated antibiotics combination with proton pump inhibitors against oral clinical isolates. The strains were identified as Staphylococcus epidermidis and Staphylococcus aureus by the 16S rRNA gene sequencing. In molecular docking, ciprofloxacin, levofloxacin, and omeprazole best fit to active pockets of transcriptional regulators 4BXI and 3QP1. None of the proton pump inhibitors were active against S. epidermidis, whereas omeprazole showed significant inhibition (MIC 3.9 μg/ml). Fluoroquinolones were active against both S. epidermidis and S. aureus. In combination analysis, a marked decrease in minimum inhibitory concentration was noticed with omeprazole (MIC 0.12 μg/ml). In antiquorum sensing experiments, a significant inhibitory zone was shown for all fluoroquinolones (14-20 mm), whereas among proton pump inhibitors, only omeprazole (12 ± 0.12 mm) was active against Chromobacterium violaceum. In combination analysis, a moderate increase in antiquorum sensing activity was recorded for ciprofloxacin, ofloxacin, and proton pump inhibitors. Further, significant S. aureus biofilm eradication was recorded using of ciprofloxacin, levofloxacin, and omeprazole combination (78 ± 2.1%). The time-kill kinetic studies indicated a bactericidal effect by ciprofloxacin: levofloxacin: omeprazole combination over 24 hrs. It was concluded that fluoroquinolone combined with omeprazole could be an effective treatment option for eradicating oral bacterial biofilms.

Evaluation of the anti-tumor activity of histone deacetylase inhibitors (HDAC6) on human pancreatic adenocarcinoma (PANC-1) cell line using a zebrafish xenograft model

Evaluation of the anti-tumor activity of histone deacetylase inhibitors (HDAC6) on human pancreatic adenocarcinoma (PANC-1) cell line using a zebrafish xenograft model

Molecular docking and antimicrobial activities of photoexcited inhibitors in antimicrobial photodynamic therapy against Enterococcus faecalis biofilms in endodontic infections

Antimicrobial photodynamic therapy (aPDT) is a promising approach to combat antibiotic resistance in endodontic infections. It eliminates residual bacteria from the root canal space and reduces the need for antibiotics. To enhance its effectiveness, an in silico and in vitro study was performed to investigate the potential of targeted aPDT using natural photosensitizers, Kojic acid and Parietin. This approach aims to inhibit the biofilm formation of Enterococcus faecalis, a frequent cause of endodontic infections, by targeting the Ace and Esp proteins. After determining the physicochemical characteristics of Ace and Esp proteins and model quality assessment, the molecular dynamic simulation was performed to recognize the structural variations. The stability and physical movement of the protein-ligand complexes were evaluated. In silico molecular docking was conducted, followed by ADME/Tox profiling, pharmacokinetics characteristics, and assessment of drug-likeness properties of the natural photosensitizers. The study also investigated the changes in the expression of genes (esp and ace) involved in E. faecalis biofilm formation. The results showed that both Kojic acid and Parietin complied with Lipinski’s rule of five and exhibited drug-like properties. In silico analysis indicated stable complexes between Ace and Esp proteins and the natural photosensitizers. The molecular docking studies demonstrated good binding affinity. Additionally, the expression of the ace and esp genes was significantly downregulated in aPDT using Kojic acid and Parietin with blue light compared to the control group. This investigation concluded that Kojic acid and Parietin with drug-likeness could efficiently interact with Ace and Esp proteins with a strong binding affinity. Hence, natural photosensitizers-mediated aPDT can be considered a promising adjunctive treatment against endodontic infections.

The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Tumors.

Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.

Effect of central metal ion on some pharmacological properties of new Schiff base complexes. Anticancer, antioxidant, kinetic/thermodynamic and computational studies

The biological capacities of Schiff Base complexes such as anti-cancer, anti-microbial and anti-oxidant properties have been widely studied in the scientific community. However, the effect of central metal ion in the occurrence of their biological properties should be paid more attention. With this aim, novel 2-(hydroxyimino)-1-phenylpropylidene)benzohydrazide (HIPB) Schiff base ligand, and C1/palladium(II), C2/platinum(II), and C3/zinc(II) complexes derived from it were synthesized and characterized. Theoretical studies showed that C2 is more reactive and also has a higher pharmacological affinity than C1 and C3. Experimental investigations were done to compare some biological properties of the complexes. The anticancer assay showed that C1-C3 have the ability to inhibit the growth of HCT116 colon cancer cell lines, but C2 shows a relatively better effect than other. Antioxidant studies using •DPPH (2,2-diphenyl-1-picrylhydrazyl) assay presented the following trend: C2 > C1 > C3 > HIPB. Considering the importance of the antioxidant enzyme catalase in removing reactive oxygen species (ROS), the interaction of C1-C3 with Bovine Liver Catalase (BLC) was evaluated. Kinetic studies showed that C1-C3 can inhibit the catalytic performance of BLC by a similar mechanism, i.e. mixed-type inhibition. Among them, C1 was the strongest inhibitor (Activity inhibition% = 82.2). The C1-C3 quenched the BLC fluorescence emission with dynamic quenching mechanism. The binding affinity to BLC was higher for C1 and C2 than C3. The most important forces in the interaction of C1-C3 with BLC were hydrophobic interactions, which was strongly confirmed by molecular docking data. Tracking the structural changes of catalase showed that BLC undergoes structural changes in the presence of C1 more than C2 and C3.

Palladium (II)-N-heterocyclic Carbene Complexes: Synthesis, Molecular Docking, UV-Vis Absorption and Enzyme Inhibition

Background: Alzheimer's disease is the most prevalent form of dementia; it affects the brain regions responsible for thought, memory, and language. Dementia cannot currently be cured by any medication. Objective: We aimed to synthesize Pd-NHC type PEPPSI and investigate their biological activity in anticholinesterase enzymes. Methods: In this study, we described preparing a series of Pd-NHC type PEPPSI obtained from their unsymmetrical benzimidazolium salts. These complexes (3a-f) were synthesized from the 2- chloromethyl-1,3-dioxalane benzimidazolium salts, PdCl2, KBr and pyridine. The compounds (3a-f) were tested against two enzymes (AChE and BChE). Results: The results showed that most of the Palladium–NHC complexes effectively inhibited AChE with IC50 values in the range of 4.94 - 40.03 μM, and for BChE are in the range of 4.21 - 21.28 μM. The results showed that the compound (3a) was the most potent inhibitor activity against both AChE and BChE. The inhibition parameter (IC50) was calculated by the spectrophotometric method. The inhibitory effects of the synthesized Pd-NHCs were compared to galantamine as a clinical cholinergic enzyme inhibitor. Additionally, Molecular docking is carried out to estimate the binding pattern between the newly synthesized compounds and both AChE and BChE active sites. Conclusion: The results demonstrated that all synthesized compounds show excellent to moderate inhibition against the examined enzymes (AChE/BChE).