Search Results (39)

Background/Objectives: Symmetrical dual-site acetylcholinesterase (AChE) inhibitors offer a compelling strategy to mitigate mutational drug resistance, yet static modeling fails to capture induced-fit dynamics under mutational stress. Methods: Here, a 100,000-compound virtual library was filtered using a machine learning-based QSAR classification pipeline. A strict, empirically calibrated Jaccard applicability domain filter (AD = 0.823) eliminated topological anomalies, yielding a robust cross-validation accuracy (ROC-AUC: 0.80 ± 0.05; independent test MCC: 0.61). Multi-parameter ADMET and shape screening prioritized unique chemotypes to probe the 20 Å enzyme gorge. All-atom explicit-solvent molecular dynamics simulations were coupled with 150 ns enhanced-sampling Metadynamics along two orthogonal collective variables (gorge depth and ligand orientation) to map out the free energy surfaces under mutational stress. Results: Symmetrical probes suffered catastrophic unbinding upon anchor loss. Conversely, the symmetrical core of Lead Compound 1631 demonstrated extraordinary structural resilience. In silico site-directed mutagenesis (W86A and W286A) triggered a thermodynamic locking effect; the W86A mutant forced the complex into a deeper energetic well (ΔG_min = 9.23 ± 1.98 kJ/mol) than the wild-type state (5.26 ± 1.69 kJ/mol). MM/GBSA decomposition confirmed an active electrostatic-solvation compensation mechanism along a “solvation see-saw” diagonal (ΔΔG_total = +1.59 kcal/mol). Finally, Dynamic Cross-Correlation Matrix analysis quantified a mechanical inversion of the CAS-PAS axis into an anti-correlated clamping mode (−0.04) that locked the ligand bridge in place. Conclusions: These results demonstrate that symmetrical dual-site targeting, combined with dynamic thermodynamic locking, provides a resilient framework to overcome mutational resistance in AChE inhibitors. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, cholinergic dysfunction, and amyloid-β (Aβ) aggregation. Tri-Sannibat-Phol (TSB), a classical Thai polyherbal formulation comprising Piper retrofractum fruit, Ocimum tenuiflorum root, and Piper nigrum root, has been traditionally used for its medicinal properties, yet its anti-AD potential has never been scientifically evaluated. Methods: The therapeutic potential of TSB was investigated through in vitro bioassays including antioxidant, acetylcholinesterase (AChE) inhibitory, and anti-Aβ aggregation assays, alongside neuroprotective evaluation in H₂O₂-induced SH-SY5Y neuroblastoma cells. Acute oral toxicity was assessed in male ICR mice in accordance with OECD Guideline 420. Cognitive-enhancing effects were evaluated using the modified Y-maze, Novel Object Recognition, and Morris Water Maze tests in a scopolamine-induced amnesic mouse model. LC-MS/MS analysis was performed for phytochemical characterization and chemical standardization of the formulation. Results: TSB demonstrated significant antioxidant activity, AChE inhibitory activity, and anti-Aβ aggregation effects, with P. nigrum and O. tenuiflorum identified as the primary contributing components. Neuroprotective effects were confirmed in H₂O₂-induced SH-SY5Y cells, where TSB significantly improved cell viability across concentrations of 1–100 µg/mL. Acute oral toxicity assessment revealed an LD₅₀ exceeding 2000 mg/kg, indicating a favorable safety profile. In vivo behavioral studies demonstrated that TSB at medium-to-high doses significantly reversed scopolamine-induced cognitive deficits across all three behavioral tests. LC-MS/MS analysis identified thirteen piperidine alkaloids, with piperine as the dominant constituent at 17.61 ± 0.80% w/w, proposed as the primary bioactive driver and chemical marker for future quality standardization. Conclusions: These findings suggest that TSB exerts multi-targeted anti-AD effects through complementary mechanisms, supporting its potential as a traditional medicine-based therapeutic candidate for further preclinical and clinical investigation. Full article

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer’s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2α kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal Aβ (iAβ) accumulated to a PKR- and/or HRI-activating concentration and designated, in terms of the ACH2.0, as a “conventional stressor”. The ensuing disease is referred to, accordingly, as “conventional AD”. Any stressor other than iAβ, which is capable of activating one or more eIF2α kinases in neuronal cells, is designated as an “unconventional stressor”. At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as “unconventional AD”, at levels of iAβ below those required for activation of PKR and/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human AβPP mRNA is eligible for this process, and its asymmetric amplification yields 5′-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in AβPP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of AβPP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the AβPP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iAβ and C99, anti-antisense oligonucleotides (AASO) for AβPP RNA, and the restructuring of the 5′ terminus of AβPP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies. Full article

Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer’s disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), represent one of the main global health challenges. Cannabis sativa synthesizes spermidine-type alkaloids, whose potential biological activities have been little studied. This study aimed to isolate bioactive alkaloids from an alkaloid-enriched extract (AEE) of C. sativa roots throughout a bioguided approach using conventional chromatographic techniques based on AChE and BuChE inhibitory activities. A qualitative and semiquantitative analysis by UPLC-ESI-MS/MS as well as molecular modeling simulations were performed. In addition, predictive in silico analyses were conducted to assess toxicity properties. The alkaloids cannabisativine (CS) and anhydrocannabisativine (ACS) were isolated, and showed highly selective BuChE inhibitory activity. The molecular modeling study revealed a conserved interaction profile across both alkaloids, indicating the amino acids TRP82, GLU197, TYR440, and HIS438 as the major contributors involved in the complex formation. Finally, CS and ACS exhibited low in silico predictive toxicity values. In conclusion, CS and ACS alkaloids emerge as new selective BuChE inhibitors with therapeutic potential that deserves the attention from the field of pharmacology in neurodegenerative disease research. Additionally, this approach promotes innovation and environmental sustainability through the use of C. sativa roots. Full article

Effective design is becoming increasingly necessary to shorten product development times to meet evolving user demands. Thus, it is essential that designers uncover user requirements and translate them into tangible product specifications, but with the added endeavour of balancing functional and sustainability requirements. This poses several challenges to designers. In early design, designers must make important decisions based on limited knowledge, risking developing products which are rejected by users. A literature review determined that no available system is sufficient to balance multi-user requirements and design characteristics. Hence, the research goal is to address the gap in design support systems, which inspired the generation of the PRioritising and achIeving Multi-user rEquirements (PRIME) framework being proposed. The contribution of this work lies in the fusion of topic modelling, sentiment analysis, and conflict resolution techniques to enhance multi-user experience. The framework prioritises multi-user and design requirements, and translates them into product specifications. Furthermore, PRIME proposes and evaluates innovative design aspects to fulfil the established design targets. This research focuses on providing a knowledge-based framework applied in the early design stages to capture multi-user requirements and lays the foundation for concept generation. A case study of smart and sustainable packaging is considered to highlight the framework’s applicability. Full article

Background and Objectives: Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by cholinergic deficits, oxidative stress, amyloid-β (Aβ) aggregation, and tau hyperphosphorylation. Caffeic acid (CA), a naturally occurring hydroxycinnamic acid, has emerged as a promising neuroprotective candidate due to its antioxidant, anti-inflammatory, and enzyme-inhibitory properties. This review systematically evaluates recent in vitro and in vivo evidence regarding the therapeutic potential of CA in AD models and examines the impact of delivery systems and derivatives on its efficacy and bioavailability. Materials and Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases, adhering to the PRISMA 2020 guidelines. Studies published between January 2021 and April 2025 were included in this review. Eligible studies investigated the effects of CA or CA-enriched extracts on AD-relevant mechanisms using in vitro, in vivo, and in silico models. After screening 101 articles, 44 met the inclusion criteria and were included in the final qualitative synthesis of the study. Results: In vitro studies have confirmed that CA modulates cholinergic activity by inhibiting AChE and BChE and exerting antioxidant and anti-amyloidogenic effects. In vivo studies using pharmacological, genetic, and metabolic AD models have demonstrated improvements in cognitive function, reduction in oxidative stress, inflammation, and Aβ and tau pathologies following CA administration. Advanced delivery platforms, such as solid lipid nanoparticles, transferrin-functionalized liposomes, and carbon dot systems, have significantly enhanced CA’s brain bioavailability and therapeutic efficacy. CA derivatives, including caffeic acid phenethyl ester and nitro-substituted analogs, exhibit improved pharmacokinetic and neuroprotective profiles. Conclusions: This review provides evidence supporting the use of CA as a promising multitarget agent against AD pathology. Its therapeutic potential is further enhanced by nanotechnology-based delivery systems and chemical modifications that overcome the limitations of bioavailability. Continued preclinical evaluation and translational studies are warranted to support its clinical development as an AD intervention. Full article

The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer’s disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD—conventional and unconventional—differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5′UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the “omnipotent” Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that “sporadic AD” is not sporadic at all (“non-familial” would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball’s chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other “…mab” or “…stat” notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently “deep”, opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents—activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5′-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with “validation” sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed. Full article

Topical formulations that include natural active compounds to treat inflamed and aching skin are favored by patients. Small local producers use commercial creams and gels to which they add compounds, often with criteria based more on trends than scientific evidence, to obtain products to treat inflamed joints or skin. Based on our previous studies that demonstrated the anti-inflammatory and analgesic effects of Harpagophytum procumbens extracts and N-acetylglucosamine, we were interested in preparing formulations with these natural substances for topical applications. In the present study, we compared the rheological properties of various creams and gels with bulk and nanoparticle forms of N-acetylglucosamine added, focusing on the flow properties of multiphase emulsion. Moreover, the ability of nanoparticles to reduce inflammation and stimulate collagen production was demonstrated in both chondrocyte and fibroblast spheroids. The results showed the activity of nano-N-acetylglucosamine in our cell models, suggesting its suitability for use as a component in creams and gels. Furthermore, its ability to affect the flow properties of commercial creams and gels makes it an ideal component of topical formulations for the treatment of inflamed skin and joints. Full article

Conotoxins are small and highly potent neurotoxic peptides derived from the venom of marine cone snails which have captured the interest of the scientific community due to their pharmacological potential. These toxins display significant sequence and structure diversity, which results in a wide range of specificities for several different ion channels and receptors. Despite the recognized importance of these compounds, our ability to determine their binding targets and toxicities remains a significant challenge. Predicting the target receptors of conotoxins, based solely on their amino acid sequence, remains a challenge due to the intricate relationships between structure, function, target specificity, and the significant conformational heterogeneity observed in conotoxins with the same primary sequence. We have previously demonstrated that the inclusion of post-translational modifications, collisional cross sections values, and other structural features, when added to the standard primary sequence features, improves the prediction accuracy of conotoxins against non-toxic and other toxic peptides across varied datasets and several different commonly used machine learning classifiers. Here, we present the effects of these features on conotoxin class and molecular target predictions, in particular, predicting conotoxins that bind to nicotinic acetylcholine receptors (nAChRs). We also demonstrate the use of the Synthetic Minority Oversampling Technique (SMOTE)-Tomek in balancing the datasets while simultaneously making the different classes more distinct by reducing the number of ambiguous samples which nearly overlap between the classes. In predicting the alpha, mu, and omega conotoxin classes, the SMOTE-Tomek PCA PLR model, using the combination of the SS and P feature sets establishes the best performance with an overall accuracy (OA) of 95.95%, with an average accuracy (AA) of 93.04%, and an f1 score of 0.959. Using this model, we obtained sensitivities of 98.98%, 89.66%, and 90.48% when predicting alpha, mu, and omega conotoxin classes, respectively. Similarly, in predicting conotoxins that bind to nAChRs, the SMOTE-Tomek PCA SVM model, which used the collisional cross sections (CCSs) and the P feature sets, demonstrated the highest performance with 91.3% OA, 91.32% AA, and an f1 score of 0.9131. The sensitivity when predicting conotoxins that bind to nAChRs is 91.46% with a 91.18% sensitivity when predicting conotoxins that do not bind to nAChRs. Full article

For at least two reasons, the current transgenic animal models of Alzheimer’s disease (AD) appear to be patently inadequate. They may be useful in many respects, the AD models; however, they are not. First, they are incapable of developing the full spectrum of the AD pathology. Second, they respond spectacularly well to drugs that are completely ineffective in the treatment of symptomatic AD. These observations indicate that both the transgenic animal models and the drugs faithfully reflect the theory that guided the design and development of both, the amyloid cascade hypothesis (ACH), and that both are inadequate because their underlying theory is. This conclusion necessitated the formulation of a new, all-encompassing theory of conventional AD—the ACH2.0. The two principal attributes of the ACH2.0 are the following. One, in conventional AD, the agent that causes the disease and drives its pathology is the intraneuronal amyloid-β (iAβ) produced in two distinctly different pathways. Two, following the commencement of AD, the bulk of Aβ is generated independently of Aβ protein precursor (AβPP) and is retained inside the neuron as iAβ. Within the framework of the ACH2.0, AβPP-derived iAβ accumulates physiologically in a lifelong process. It cannot reach levels required to support the progression of AD; it does, however, cause the disease. Indeed, conventional AD occurs if and when the levels of AβPP-derived iAβ cross the critical threshold, elicit the neuronal integrated stress response (ISR), and trigger the activation of the AβPP-independent iAβ generation pathway; the disease commences only when this pathway is operational. The iAβ produced in this pathway reaches levels sufficient to drive the AD pathology; it also propagates its own production and thus sustains the activity of the pathway and perpetuates its operation. The present study analyzes the reason underlying the evident inadequacy of the current transgenic animal models of AD. It concludes that they model, in fact, not Alzheimer’s disease but rather the effects of the neuronal ISR sustained by AβPP-derived iAβ, that this is due to the lack of the operational AβPP-independent iAβ production pathway, and that this mechanism must be incorporated into any successful AD model faithfully emulating the disease. The study dissects the plausible molecular mechanisms of the AβPP-independent iAβ production and the pathways leading to their activation, and introduces the concept of conventional versus unconventional Alzheimer’s disease. It also proposes the path forward, posits the principles of design of productive transgenic animal models of the disease, and describes the molecular details of their construction. Full article

Alzheimer’s disease (AD) is a complicated disease for which there are still no ideal one-target drugs, while multi-target drugs are closer to ideal drugs and will provide new solutions for the clinical treatment of AD. DL0410 is a promising multi-target drug candidate for AD treatment that is not only a significant inhibitor against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) but also an antagonist of histamine H3 receptor (H3R), and its therapeutic efficacy in treating cognitive dysfunction has been validated in a series of AD-related animal models, including scopolamine-induced mice, D-galactose-induced and Aβ-induced mice, and APP/PS1 and SAMP8 mice. Although the structure of DL0410 has been analyzed using various detection techniques, such as MS and NMR, its three-dimensional crystal structure still requires further confirmation. In this study, the crystal of DL0410 was grown in aqueous solution, and its structure was detected using the X-ray diffraction method. The crystal data, atomic coordinates, bond lengths, angles, and hydrogen bonds of DL0410 were obtained. Its stability was proven by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Based on this study, the molecular docking of DL0410 with AChE, BuChE, and H3R was performed to uncover their interaction mechanisms and explain their bioactivities. This study provides important information for new multi-target drug design and the research and development of new drugs for AD treatment. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in cholinergic transmission, formation of extracellular deposits of β-amyloid peptide, and accumulation of deposits of a phosphorylated form of the TAU protein. The currently available drugs are prescribed for symptomatic treatment and present adverse effects such as hepatotoxicity, hypertension, and weight loss. There is urgency in finding new drugs capable of preventing the progress of the disease, controlling the symptoms, and increasing the survival of patients with AD. This study aims to present new multipurpose compounds capable of simultaneously inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BChE)—responsible for recycling acetylcholine in the synaptic cleft—and beta-secretase 1 (BACE-1)—responsible for the generation of amyloid-β plaques. AChE, BChE, and BACE-1 are currently considered the best targets for the treatment of patients with AD. Virtual hierarchical screening based on a pharmacophoric model for BACE-1 inhibitors and a dual pharmacophoric model for AChE and BChE inhibitors were used to filter 214,446 molecules by QFIT_BACE > 0 and QFIT_DUAL > 56.34. The molecules selected in this first round were subjected to molecular docking studies with the three targets and further evaluated for their physicochemical and toxicological properties. Three structures: ZINC45068352, ZINC03873986, and ZINC71787288 were selected as good fits for the pharmacophore models, with ZINC03873986 being ultimately prioritized for validation through activity testing and synthesis of derivatives for SAR studies. Full article

Alzheimer’s disease (AD) is a neurodegenerative disease that affects the majority of people worldwide. To date, there is no cure for the disease, so new therapeutic targets need to be identified and studied. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD treatment. In order to identify new inhibitors, a newly synthesized series containing thirty seven 2-hydroxy-N-phenylbenzamidederivatives were tested to study the inhibition of enzymes associated with this disease. Our work focuses on the use of molecular modeling methods based on molecular docking, QSAR and ADME property prediction. Our molecular docking results discussion is based on a number of parameters. Analysis of these obtained results showed that the ligands L18, L17 and L6 have a high inhibitory effect in the case of the enzyme AChE, while the ligands L6′, L30′ and L4′ have a high inhibitory effect in the case of the enzyme BuChE. In addition, the ADME-T properties calculation proved that these ligands respect the Lipinski, Veber and Egan rules, allowing us to select them as being probably the best inhibitors of Alzheimer’s disease (AD). Then, a QSAR model was developed to explain and predict the inhibitory activity of a series of compounds using different descriptors. This model has been validated by two methods: internal and external. Full article

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC₅₀ = 0.13 ± 0.04 μM) and butyrylcholinesterase (BuChE, IC₅₀ = 6.11 ± 0.15 μM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aβ aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aβ. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1β, TNF-α; IC₅₀ = 0.62 ± 0.07 μM, 1.78 ± 0.21 μM, 1.31 ± 0.28 μM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood–brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD. Full article