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The search for effective anti-cancer therapies has led to the exploration of dual inhibition strategies targeting multiple key molecular pathways. In this study, we aimed to design a novel candidate capable of dual inhibition targeting both EGFR (Epidermal Growth Factor Receptor) and PARP-1 (poly(ADP-ribose)polymerase-1), two crucial proteins implicated in cancer progression and resistance mechanisms. Through molecular hybridization and structure-based drug design approaches, we synthesized a series of compounds based on spirooxindole with triazole scaffolds with the potential for dual EGFR and PARP-1 inhibition. Interestingly, compounds 4a, 4b and 4f showed potent cytotoxicity against HepG2 cells with IC 50 values of 3.6, 4.6, and 1.9 μM compared to doxorubicin (IC 50 = 2.78 μM), with poor cytotoxicity against THLE2 cells with IC 50 values higher than 40 μM in a selective way. They exhibited potent EGFR and PARP-1 inhibition with IC 50 values of 74.6, 85.3, and 116.1 nM compared to Erlotinib (IC 50 = 80 nM, 94.7%). Additionally, they exhibited potent PARP-1 inhibition, with IC 50 values of 2.01, 3.6, and 18.4 nM compared to Olaparib (IC 50 = 1.49 nM, 94.5%). Furthermore, compound 4a-treatment induced increased apoptosis by 6.6-fold, as the effective cell death mechanism. Overall, our study underscores the importance of multi-targeted approaches in developing effective anti-cancer agents., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: Quinoline scaffolds are serving as the core structure for numerous antifungal, analgesic, antipyretic, anti-inflammatory drugs as well as have also been investigated for their potential antidiabetic properties. Though further exploration is required in this area as the current antidiabetic agents, such as acarbose, miglitol and voglibose, are associated with several adverse side effects. In this context, arylated tetrahydrobenzo[ H ]quinoline-3-carbonitrile derivatives were designed and evaluated as potential antidiabetic agents. Materials & methods: A one-pot multicomponent reaction of 6-methoxy-1-tetralone with ethyl cyanoacetate, ammonium acetate and varying aldehydes yielded a range of new arylated tetrahydrobenzo[ h ]quinoline-3-carbonitrile molecules 1-36 . Results: Compounds 2-5 , 12 , 13 , 19 and 32-34 showed excellent inhibition against α-amylase (IC 50  = 3.42-15.14 μM) and α-glucosidase (IC 50  = 0.65-9.23 μM) enzymes in comparison to the standard acarbose (IC 50  = 14.35 μM). In addition, all compounds revealed significant to moderate DPPH radical scavenging activity (SC 50  = 21.30-138.30 μM) compared with BHT (SC 50  = 64.40 μM). Kinetic studies confirmed competitive inhibition mode, while molecular docking studies comprehend ligands' interaction with enzyme's active sites and absorption, distribution, metabolism, and excretion analysis confirms that all synthetic derivatives are nontoxic. Conclusion: This research offers a range of lead candidates to become antidiabetic agents after further advanced study.

Despite the waning threat of the COVID-19 pandemic, its detrimental impact on global health persists. Regardless of natural immunity or immunity obtained through vaccination, emerging variants of the virus continue to undergo mutations and propagate globally. The persistent mutations in SARS-CoV-2, along with the subsequent formation of recombinant sub-variants has become a challenge for researchers and health professionals, raising concerns about the efficacy of current vaccines. Gaining a better understanding of the biochemical interactions between the Spike Protein (RBD) of SARS-CoV-2 variants and the human ACE2 receptor can prove to be beneficial in designing and developing antiviral therapeutics that are equally effective against all strains and emerging variants. Our objective in this study was to investigate the interfacial binding pattern of the SARS-CoV-2 RBD-ACE2 complex of the Wild Type (WT), Omicron, and the Omicron recombinant sub-variant XBB.1.16. We aimed to examine the atomic level factors and observe how mutations influence the interaction between the virus and its host using Molecular Dynamics simulation, MM/GBSA energy calculations, and Principal Component Analysis. Our findings reveal a higher degree of structural deviation and flexibility in XBB.1.16 compared to WT and Omicron. PCA indicated a wider cluster and significant flexibility in the movements of XBB.1.16 which can also be observed in free energy landscapes, while the normal mode analysis revealed converging motions within the RBD-ACE2 complexes which can facilitate the interaction between them. A pattern of decreased binding affinity was observed in case of XBB.1.16 when compared to the WT and Omicron. These observed deviations in XBB.1.16 when compared to its parent lineage Omicron, and WT can be attributed to the mutations specific to it. Collectively, these results enhance our understanding of the impact of mutations on the interaction between this strain and the host, taking us one step closer to designing effective antiviral therapeutics against the continually mutating strains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC 50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC 50  = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC 50  = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC 50  = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC 50  = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC 50  = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4. Molecular structures were encoded into bit arrays, serving as molecular fingerprints, which were subsequently analyzed using the Bayesian network algorithm to identify patterns for screening the data. The shortlisted hits obtained via machine learning protocols were further validated by Molecular Docking and via ADME and Toxicity predictions. The shortlisted compounds were then subjected to MD Simulations of the membrane-bound FFAR4-ligand complexes for 100 ns each. Molecular analyses, encompassing binding interactions, RMSD, RMSF, RoG, PCA, and FEL, were conducted to scrutinize the protein-ligand complexes at the inter-atomic level. The analyses revealed significant interactions of the shortlisted compounds with the crucial residues of FFAR4 previously documented. FFAR4 as part of the complexes demonstrated consistent RMSDs, ranging from 3.57 to 3.64, with minimal residue fluctuations 5.27 to 6.03 nm, suggesting stable complexes. The gyration values fluctuated between 22.8 to 23.5 nm, indicating structural compactness and orderliness across the studied systems. Additionally, distinct conformational motions were observed in each complex, with energy contours shifting to broader energy basins throughout the simulation, suggesting thermodynamically stable protein-ligand complexes. The two compounds CHEMBL2012662 and CHEMBL64616 are presented as potential FFAR4 agonists, based on these insights and in-depth analyses. Collectively, these findings advance our comprehension of FFAR4's functions and mechanisms, highlighting these compounds as potential FFAR4 agonists worthy of further exploration as innovative treatments for metabolic and immune-related conditions., (© 2024. The Author(s).)

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC 50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC 50  = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC 50  = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC 50  = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC 50  = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC 50  = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC 50  = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Introduction: Transient ischemic attack (TIA) and minor ischemic stroke (IS) is associated with a increased risk of late life dementia. In this study we aim to study the extent to which the rates of hippocampal atrophy in TIA/IS differ from healthy controls, and how they are correlated to neuropsychological measurements., Methods: TIA or minor stroke patients were tested with a neuropsychological battery including tests of executive function, and verbal and non-verbal memory at three time points out to 3 years. Annualized rates of hippocampal atrophy in TIA/IS patients were compared to controls. A linear-mixed regression model was used to assess the difference in rates of hippocampal atrophy after adjusting for time and demographic characteristics., Results: TIA/IS patients demonstrated a higher hippocampal atrophy rate than healthy controls over a 3-year interval: the annual percentage change of the left hippocampal volume was 2.5% (78 mm 3 per year (SD 60)) for TIA/IS patients compared to 0.9% (29 mm 3 per year (SD 32)) for controls ( p  < 0.01); and the annual percentage change of the right hippocampal volume was 2.5% (80 mm 3 per year (SD 46)) for TIA/IS patients compared to 0.5% (17 mm 3 per year (SD 33)) for controls ( P  < 0.01). Patients with higher annual hippocampal atrophy were more likely to report higher TMT B times, but lower ROC total score, lower California Verbal Learning Test-II total recall, and lower ROC Figure recall scores longitudinally., Conclusion: TIA/IS patients experience a higher rate of hippocampal atrophy independent of TIA/IS recurrence that are associated with changes in episodic memory and executive function over 3 years., Competing Interests: None, (© 2021 Published by Elsevier B.V.)

Patently, Protein-Protein Interactions (PPIs) lie at the core of significant biological functions and make the foundation of host-pathogen relationships. Hence, the current study is aimed to use computational biology techniques to predict host-pathogen Protein-Protein Interactions (HP-PPIs) between MRSA and Humans as potential drug targets ultimately proposing new possible inhibitors against them. As a matter of fact this study is based on the Interolog method which implies that homologous proteins retain their ability to interact. A distant homolog approach based on Interolog method was employed to speculate MRSA protein homologs in Humans using PSI-BLAST. In addition the protein interaction partners of these homologs as listed in Database of Interacting Proteins (DIP) were predicted to interact with MRSA as well. Moreover, a direct approach using BLAST was also applied so as to attain further confidence in the strategy. Consequently, the common HP-PPIs predicted by both approaches are suggested as potential drug targets (22%) whereas, the unique HP-PPIs estimated only through distant homolog approach are presented as novel drug targets (12%). Furthermore, the most repeated entry in our results was found to be MRSA Histone Deacetylase (HDAC) which was then modeled using SWISS-MODEL. Eventually, small molecules from ZINC, selected randomly, were docked against HDAC using Auto Dock and are suggested as potential binders (inhibitors) based on their energetic profiles. Thus the current study provides basis for further in-depth analysis of such data which not only include MRSA but other deadly pathogens as well., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Amiodarone is prescribed for certain cardiac arrhythmias in current medical practice. The drug targets and inhibits voltage dependent sodium (Na+ v), calcium (Ca+2 v), potassium (K+ v) channels, enzymes like cytochrome P450 and oxidosqualene cyclase. Past studies have shown that amiodarone exerts antiparasitic effects against Trypanosoma cruzi and Acanthamoeba castellanii., Objectives: The presence of aforementioned targets and the type of cell death induced by amiodarone in pathogenic eukaryotes like Acanthamoeba castellanii remains to be established. We inferred the presence of homologous targets of amiodarone in A. castellanii compared with humans., Methods: This study used bioinformatics exploration for amino acid sequence homology, ligand binding attribute predictions, 3D structural model development, and experimental assays that highlight similarity between certain target proteins in Acanthamoeba as compared to humans., Results: The sequence identity scores for amino acids and 3D models show that A. castellanii expresses similar types of targets of amiodarone like Na+ v - K+1 v channels, cytochrome P450 3A4, and lanosterol synthase (oxidosqualene cyclase). We show that even though human like L-type and two pore Ca+2 channels are present in A. castellanii, there was no evidence of the expression of T-type voltage dependent Ca+2 channels. Growth assays showed amoebicidal and amoebistatic effects at doses of 40-80μg/ml., Conclusion: The existing bioinformatics tools, ligand binding attribute prediction, and model building offer a specific method to establish homology of proteins, discover drug targets, and facilitate the investigation of the evolution of several types of cardinal ion channels from unicellular eukaryotes to multicellular species as humans., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)