Search Results (239)

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β aggregation, mitochondrial stress, and aberrant kinase activity. Carotenoids, naturally occurring pigments with antioxidant and neuroprotective properties, have emerged as promising candidates for AD intervention. In this study, we performed a systematic stepwise computational screening of a large carotenoid library (n = 1191) to identify multitarget candidates against AD–related proteins. The workflow consisted of predefined ADMET filtering (oral absorption > 90%, Caco-2 > 0.9, logBB > −1, and absence of major CYP inhibition and toxicity alerts), reducing the dataset to 61 compounds, followed by multi-target molecular docking against AChE, BChE, BACE-1, MAO-B, and GSK3-β. Compounds were ranked using an aggregated mean docking score across all five targets, and the top-performing candidate was subjected to detailed mechanistic analyses. Hopkinsiaxanthin emerged as the highest-ranked multitarget carotenoid and was further evaluated using frontier molecular orbital (FMO) analysis, pharmacophore modeling, 100 ns molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and per-residue decomposition. Docking predicted favorable estimated binding affinities toward all targets. MD simulations confirmed stable receptor–ligand complexes with low RMSD values (0.278–0.285 nm). MM/PBSA analysis indicated favorable binding free energies, particularly for GSK3-β (−22.73 kcal/mol) and AChE (−21.50 kcal/mol). Per-residue decomposition identified key hotspot residues driving stabilization. Overall, this structured computational framework identifies Hopkinsiaxanthin as a promising multitarget scaffold and supports its prioritization for experimental validation in AD models. Full article

Alpha-mangostin (AM), a xanthone from Garcinia mangostana, has shown promising nephroprotective properties, but its mechanisms in acute kidney injury (AKI) remain incompletely defined. In this study, we applied an integrative network pharmacology pipeline combined with molecular docking to clarify AM’s multi-target mechanisms in AKI. We identified 128 predicted AM targets and intersected them with AKI-related genes, yielding 122 shared targets. Protein–protein interaction analysis identified ten hub genes—TNF, AKT1, IL6, SRC, CTNNB1, HSP90AA1, NFKB1, HIF1A, PPARG, and PTGS2—implicating inflammatory, hypoxia, and cell-survival pathways. KEGG enrichment highlighted HIF-1 signaling, PI3K–Akt signaling, chemokine signaling, AGE–RAGE signaling, and pathways related to cellular senescence and oxidative stress, while GO terms emphasized responses to chemical/oxygen-containing compounds, kinase activity, signal transduction, and apoptosis. Molecular docking against the ten hub proteins showed favorable binding energies across multiple targets. The strongest predicted affinities were observed for PTGS2 (−11.13 kcal/mol), TNF (−9.74 kcal/mol), and AKT1 (−9.48 kcal/mol). Docking positioned AM within the COX-2 catalytic pocket, engaging key catalytic and hydrophobic residues similar to known inhibitors. MD simulation interaction analysis confirmed that AM maintained stable contacts with key human PTGS2 residues, characterized by dominant hydrogen bonds and water-bridge interactions with SER353, TYR355, ARG513, and SER530, along with consistent hydrophobic contacts, and persistent interactions sustained throughout the 200 ns trajectory. Collectively, these results suggest that AM modulates interconnected inflammatory, hypoxic, and survival pathways relevant to AKI, acting as a multi-target ligand with notable interaction involving COX-2, TNF, and AKT1. Further experimental validation and formulation strategies to improve bioavailability are recommended for the advancement of AM toward therapeutic evaluation in AKI. Full article

Polygonatum odoratum, a medicinal and edible plant widely used in traditional Chinese medicine and daily diets, has potential in managing various disorders, but its anti-pruritic mechanisms remain unclear. This study aimed to explore its multi-target anti-pruritic effects by integrating network pharmacology, molecular docking, molecular dynamics (MD) simulations, GeneMANIA functional association analysis (GMFA), and GEO dataset validation. Bioactive components and pruritus-related targets were identified from public databases, and interaction networks between Polygonatum odoratum and pruritus targets, as well as the antihistamine levocetirizine, were constructed. Core targets were screened, and functional enrichment analyses were performed using DAVID and KEGG. Molecular docking (AutoDock Vina) and MD simulations (AMBER20) assessed the binding energy and stability of core components with key targets. The analysis identified 5 active components, 208 related targets, and 113 pruritus-associated targets, including 10 core targets. Enrichment analysis highlighted the PI3K/Akt and IL-17 signaling pathways, while MCODE clustering suggested involvement in arachidonic acid metabolism and serotonergic synapse. GMFA supported these findings. Molecular docking showed strong binding energy (<−5 kcal/mol), and MD simulations confirmed stable ligand–target complexes. GEO dataset validation reinforced key results. This study suggests that Polygonatum odoratum may exert anti-pruritic effects through the combined actions of inflammation suppression, skin barrier repair, and neural modulation, revealing a novel multi-target mechanism for pruritus therapy and potential synergy with levocetirizine. Full article

Chronic non-healing wounds, prevalent in diabetic and vascular diseases, arise from dysregulated chemokine signaling that disrupts angiogenesis, immune coordination, and tissue remodeling. This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across the hemostasis, inflammation, proliferation, and remodeling phases. We detail chemokine classification (CC, CXC, CX3C, and C families), receptor interactions, and downstream pathways, including G protein-dependent and β-arrestin-biased mechanisms. Furthermore, we evaluate emerging therapeutic strategies, including neutralizing antibodies, receptor antagonists, engineered chemokines, and biomaterial-based delivery systems designed to restore chemokine gradient integrity and promote healing. Recent advances in structural biology and protein engineering are highlighted as enabling the design of biased ligands and multi-target inhibitors to overcome chemokine redundancy. The review concludes that precision modulation of chemokine networks offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management. Full article

Alzheimer’s disease (AD) remains a significant global health challenge, highlighting the need for novel dual inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This study investigated the trunk bark of Terminalia triptera Stapf. as a potential source of bioactive secondary metabolites for AD management. Bioassay-guided isolation led to the identification of two flavan-3-ol derivatives, epicatechin-(4β→8)-ent-catechin (1) and (−)-catechin (2), reported here for the first time from this species. In vitro assays demonstrated that the dimeric compound 1 exhibited stronger dual inhibitory activity against AChE and BChE, with IC₅₀ values of 4.41 × 10⁻⁴ and 4.75 × 10⁻⁴ mol/L, respectively, surpassing the reference compound berberine chloride. Molecular docking analysis revealed that compound 1 formed extensive interactions within both catalytic and peripheral anionic sites of the enzymes. Density Functional Theory (DFT) calculations indicated high kinetic stability, reflected by large HOMO–LUMO energy gaps (6.66–6.97 eV), while global reactivity descriptors suggested lower electrophilicity (ω = 2.19–2.34 eV), supporting a potentially favorable safety profile. Furthermore, 100 ns molecular dynamics simulations confirmed stable ligand–protein complexes stabilized by hydrogen-bond networks and deep binding within catalytic pockets. Overall, these findings highlight T. triptera and its dimeric proanthocyanidins as promising multi-target candidates for anti-Alzheimer drug development. Full article

Background: Dengue virus (DENV) does not have any effective antiviral therapy. The Cinnamomum verum has cinnamic acid and oleic acid that could inhibit important viral proteins. Aim: To compare their inhibitory capacity with the key DENV proteins through molecular docking, molecular dynamics and in silico ADMET. Methods: Phytochemical profiling of the ethanolic extract of the bark was done by GCMS. AutoDock Vina (version 1.2.0) was used to dock cinnamic acid and oleic acid to key proteins of DENV (NS5, NS3, and envelope) in the presence of ribavirin as the reference. The best complexes were then subjected to 50 ns of molecular dynamics simulation and stability measured by RMSD, RMSF, Rg, SASA, hydrogen bonding and RDF. Validated in silico tools were used to predict the ADMET properties. Results: Analysis of GC–MS revealed cinnamic acid (85.92%) and oleic acid (5.33%). The outcome of docking was that the cinnamic acid had the greatest affinity with NS5 (−5.970 kcal/mol) and the capsid protein (−5.755 kcal/mol), and oleic acid showed the highest affinity with the capsid (−6.150 kcal/mol) and then with NS5 (−5.209 kcal/mol). Both ligands had a relatively weak interaction with NS3. Simulation of the molecular dynamics showed the stability of the top complexes, especially the cinnamic acid–NS5 complex, that retained low RMSD (1.6–1.9 A), stable Rg and SASA profiles, and continued hydrogen bonding during the 50 ns period. The use of cinnamic acid in ADMET projections was more preferable, as it was more soluble, orally bioavailable (0.91), and drug-like (QED 0.65), but oleic acid revealed higher lipophilicity and lower drug-like properties (QED 0.29). Conclusions: Cinnamic acid showed specificity towards the NS5 proteins with the help of stable dynamics and good predicted pharmacokinetics, which are features that make it a promising multi-target anti-DENV scaffold. Oleic acid exhibited poor affinity and poor pharmacokinetic properties. The findings are predictive and must be validated using biochemical, cellular, and toxicological means to prove the antiviral efficacy and safety. Full article

Background/Objectives: The medical mushroom Ophiocordyceps sinensis (Caterpillar Fungus), known for its ability to enhance “vitality,” is one of the most popular medicines in Asian traditional medical systems. According to the Chinese Pharmacopeia, O. sinensis is standardized for its adenosine content, the precursor of ATP, which mediates numerous physiological and pathological processes in many diseases. The related fungus of order Hypocreales, Cordyceps militaris, and its major bioactive constituents, 3′-deoxyadenosine (cordycepin), also exhibit pleiotropic biological activities. This review aims to provide a rationale for the adaptogenic and resilience-supporting effects of these medicinal fungi and to align food and drug regulation in Western countries. Methods: In this narrative review, we integrated results from chemical, pharmacokinetic, network pharmacology, preclinical, and clinical studies of O. sinensis, C. militaris, and cordycepin using network pharmacology and bioinformatics tools. Results: Across studies, recurrent mechanistic hubs included PI3K–Akt, AMPK–mTOR, MAPK, NF-κB, apoptosis, and adaptive stress-response signaling pathways, linking immune regulation and metabolic homeostasis. Experimental studies confirmed modulation of cytokine production, kinase signaling, and mitochondrial regulators. Clinical meta-analyses demonstrate consistent adjunctive benefits in renal and pulmonary disorders, although heterogeneity in preparation and methodological limitations remains significant. The review reveals controversy regarding the bioavailability of cordycepin in vivo and its concentration in vitro studies, raising the hypothesis that cordycepin may act as a driver, triggering the organism’s adaptive stress response in stress-induced and aging-related diseases. Pharmacokinetic data indicate that systemic cordycepin concentrations after oral administration remain in the nanomolar range, suggesting that some predicted molecular interactions may occur indirectly or through systems-level mechanisms. The review, for the first time, suggests establishing a regulatory category for resilience-supporting physiological modulators to align food and drug regulation in the EU with contemporary systems biology, thereby complementing the work of EFSA, EMA, FDA, and Asian authorities. Conclusions:O. sinensis, C. militaris, and 3-deoxyadenosine share a common adaptogenic mechanism for maintaining homeostasis of cellular and integrated biological system functions. The systems-level network analysis and reductionistic molecular ligand preceptor pharmacology provide complementary approaches for understanding the multi-target bioactivity of these fungi. This review clarifies conceptual and regulatory barriers to recognizing resilience-supporting interventions and informs future regulatory innovation. Full article

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC₅₀ = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC₅₀ = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC₅₀ = 0.102 ± 0.005 µM) and CA XII (IC₅₀ = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G₂/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms. Full article

Background: Chrysopogon zizanioides (L.) Roberty (vetiver) is a perennial medicinal grass with deep aromatic roots traditionally used for several ailments. Its root essential oil (CZEO) is rich in phytochemicals with documented antimicrobial, anti-inflammatory, and antioxidant activities. Although its anticancer potential remains underexplored, the complex phytochemical profile of CZEO positions it as a promising multi-target therapy, particularly for colorectal (CRC) and lung cancers where resistance and pathway redundancy often limit conventional treatments. Therefore, this study aimed to investigate the phytochemical composition and antiproliferative activity of CZEO from Qatar against colorectal (HCT-116) and lung (A549) cancer cells and to elucidate its molecular targets and mechanisms of action in CRC and lung cancer using network pharmacology and in silico approaches. Methods: CZEO was extracted by steam distillation and characterized using GC–MS. In vitro proliferation assays with HCT-116 colorectal and A549 lung cancer cells were conducted using the Alamar Blue assay. The ten most abundant phytochemicals identified by GC–MS were assessed for drug-likeness and ADMET properties and further analyzed through network pharmacology, molecular docking, and molecular dynamics (MD) simulations to elucidate the molecular targets and mechanisms underlying CZEO’s anticancer activity. Results: GC-MS profiling identified 40 compounds, predominantly sesquiterpenoids (93%), including khusimol, β-eudesmol, α-vetivone, and rosifoliol. CZEO inhibited cancer cell viability in a dose-dependent manner, with IC₅₀ values of 62.95 ± 2.19 µg/mL for HCT-116 and 167.82 ± 6.51 µg/mL for A549 cells, demonstrating greater potency against colorectal cancer. CZEO did not affect the growth of normal human neonatal fibroblasts (HDFn), suggesting potential selectivity for cancerous cells. ADMET predictions indicated favorable pharmacokinetics and low toxicity of CZEO’s top 10 abundant compounds (TACs). Network pharmacology revealed 373 and 394 overlapping gene targets between TACs and lung and colorectal cancer, respectively. The overlapping genes were used to construct a protein–protein interaction (PPI) network to identify hub genes. STAT3 and AKT1 consistently emerged as common top-scoring hub genes in both cancers. Molecular docking of TACs showed strong binding affinities of rosifoliol and α-vetivone to AKT1 (−6.20 and −5.93 kcal/mol, respectively) and STAT3 (−5.19 and −5.09 kcal/mol, respectively), surpassing reference inhibitors. MD simulations confirmed stable ligand–protein interactions and structural stabilization, particularly with α-vetivone. Conclusions: CZEO from Qatar exhibits potent antiproliferative activity against colorectal and lung cancer cells, supported by a sesquiterpenoid-rich phytochemical profile. Integrative computational analyses highlight AKT1 and STAT3 as key molecular targets, with rosifoliol and α-vetivone emerging as promising lead compounds. These findings support CZEO as a natural, multi-target anticancer agent, warranting further mechanistic and in vitro and in vivo validation. Full article

Background: To battle the side effects of anticancer Pt(II) drug cisplatin, the development of photoactivatable and/or intracellular reduction-activatable Pt(IV) prodrugs has become a promising strategy. Methods: Herein, two novel Pt(IV) prodrugs, namely, cis,cis,trans-[Pt^IV(NH₃)₂(Cl)₂(OH)(probenecid)]) (SPP) and cis,cis,trans-[Pt^IV(NH₃)₂(Cl)₂(probenecid)₂] (DPP) bearing mono- and di-probenecid at the axial positions of oxoplatin have been synthesized via covalently linking of carboxylate group in probenecid, which is a well-established clinic drug by inhibiting organic anion transporter 1 (OAT1) to reduce cisplatin-induced nephrotoxicity, with the axial hydroxyl group(s) in oxoplatin. The promising cytotoxicity of SPP and DPP against MCF-7, T47D breast cancer cells and the MDA-MB-231 triple-negative breast cancer cells was evaluated, and the mechanism of action of the two Pt(IV) prodrugs was investigated by apoptosis assay and Western blot assay. Results: SPP exhibits a comparable cytotoxicity to cisplatin against MCF-7 and T47D breast cancer cells, while it shows 2.1-fold higher cytotoxicity than cisplatin against MDA-MB-231 cells. DPP was shown to be more cytotoxic than SPP, and exhibits 8.7-, 7.5-, and 2.3-fold higher cytotoxicity than cisplatin against MCF-7, T47D, and MDA-MB-231 cells, respectively. Apoptosis assays revealed a similar early-apoptotic cell death mechanism to cisplatin for both SPP and DPP. The enhanced cellular and nuclear uptake of DPP compared to cisplatin contributes to its promising anticancer efficacy. DPP can bind to OAT1 in cancer cells, which may synergistically enhance the cytotoxicity of the Pt(IV) anticancer prodrugs. Conclusions: The direct conjugation of probenecid to the axial positions of oxoplatin confers the resulting Pt(IV) prodrugs a multitargeting property, significantly promoting the cytotoxicity of the resulting Pt(IV) complexes. This finding provides a practical strategy for drug design and cancer treatment based on platinum complexes. Full article

Fowl adenoviruses (FAdVs) represent a major threat to poultry health, with serotypes FAdV-1 and FAdV-4 causing adenoviral gizzard erosion (AGE) and hepatitis-hydropericardium syndrome (HHS), respectively. A wide variety of afflicted birds, including chicken, pigeon, and psittacine species, have been reported to carry aviadenoviruses. The disease is highly contagious and spreads rapidly between flocks and farms through vertical and horizontal transmission. In this study, we implemented a multi-stage computational drug-discovery pipeline to identify natural inhibitors of the viral fiber proteins for both FAdV-1 and FAdV-4. A curated library of 7523 natural compounds from the African Natural Products Database (ANPDB) and the South African Natural Compounds Database (SANCDB) was subjected to ADMET-based filtering, molecular docking, ADMET prediction, and 500 ns molecular dynamics simulations against four structural targets: Fiber-1 and Fiber-2 of FAdV-4, and the Short and Long Fibers of FAdV-1. Three ligands, ANPDB_6449 (−10.3 kcal/mol), ANPDB_2908 (−10.2 and −10.0 kcal/mol), and SANCDB_245 (−9.2 kcal/mol), consistently emerged as strong candidates across the entire computational workflow. While ANPDB_2908 demonstrated notable multi-target capability by binding to fiber proteins from both FAdV-1 and FAdV-4, ANPDB_6449 and SANCDB_245 exhibited strong serotype-specific potential, supported by stable interaction profiles and favorable drug-likeness characteristics. Together, these compounds highlight promising natural scaffolds for the development of targeted antiviral interventions against pathogenic FAdV serotypes. Full article

Background: The growing recognition of shared molecular pathways and molecular signatures between cardiovascular diseases and cancer has motivated interest in exploring antihypertensive-associated chemical space for oncological applications. Concurrently, artificial intelligence (AI)-driven molecular generation has enabled the rapid creation of virtual lead candidates for specific therapeutic indications, although their broader biological interaction profiles often remain unexplored. Methods: In this paper, we explore the computational screening of a library of AI-generated antihypertensive virtual lead compounds to evaluate their polypharmacological anticancer potential. The compounds were originally designed and prioritized for modulating $\mathsf{\beta }$-adrenergic receptors but are here re-evaluated in a cancer-focused context using a multi-stage in silico approach. We chose five (5) known cancer target proteins and performed compound profiling for drug-likeness, pharmacokinetic suitability, and safety. Docking simulations, binding free energy estimates, molecular interaction mapping, and pharmacophore modeling were used to evaluate the molecules’ interactions with the cancer-linked protein targets. We employed the binding free energy estimates of the ligand–protein complexes to determine compounds with polypharmacological anticancer potential. In addition, molecular dynamics simulations of some of the compounds with polypharmacological anticancer potential were employed to evaluate binding stability and dynamic behavior of selected ligand–target complexes. Results: Several compounds showed good docking scores, physicochemical characteristics, and pharmacokinetic profiles. Also, the results reveal that several AI-generated antihypertensive virtual leads exhibit favorable multi-target binding profiles, with consistent docking affinities and stable interaction networks across multiple cancer-related targets. Conclusions: Our findings suggest that several of the hypothetically evaluated compounds exhibit favorable physicochemical properties, acceptable predicted pharmacokinetic and safety profiles, and consistent predicted binding affinities across multiple cancer-relevant targets. Full article

Background: Skin cancer progression is driven by the dysregulation of key oncogenic signaling pathways, including EGFR, BRAF V600E, and TGF-β, which collectively promote tumor proliferation, invasion, and metastatic progression. Targeting these pathways using multitarget natural modulators represents a promising therapeutic strategy. Methods: In this study, forty-nine phytoconstituents from Cannabis sativa were evaluated using an integrated computational approach to explore their inhibitory potential against EGFR, BRAF V600E, and the TGF-β receptor. Molecular docking was performed to assess binding affinities and interaction profiles, followed by ADMET analysis to evaluate pharmacokinetic and safety properties. The top-ranked compounds were further investigated using 200 ns molecular dynamics simulations and MM-GBSA binding free energy calculations to assess the stability and strength of protein–ligand interactions. Results: Several phytoconstituents exhibited strong binding affinities toward the target proteins, formed stable interactions with key active-site residues, and demonstrated favorable pharmacokinetic profiles with acceptable safety characteristics. Molecular dynamics simulations confirmed the structural stability of the selected protein–ligand complexes, while MM-GBSA analysis supported their favorable binding energetics. Conclusions: These findings suggest that Cannabis sativa phytoconstituents may represent a promising source of multitarget modulators capable of attenuating EGFR, BRAF V600E, and TGF-β driven oncogenic signaling in skin cancer. This study provides a mechanistic framework that supports further in vitro validation and the development of cannabis-derived therapeutic candidates for targeted skin cancer management. Full article

A new series of tacrine–coumarin hybrids (compounds 15a–18b) linked by 1,2,3-triazole had been designed and synthesized as multifunctional ligands for the treatment of Alzheimer’s disease (AD). The inhibitory effects of the synthesized compounds on AChE and BuChE, their ability to inhibit Aβ aggregation, and their MAO inhibitory activities were evaluated. In vitro studies showed that some of the hybrids (compounds 17a–18b) exhibited significant abilities to inhibit both AChE and BuChE, self-induced Aβ aggregation, and MAO-B. In particular, compound 17d showed a well-balanced inhibitory profile against AChE and BuChE (IC₅₀ = 0.080 ± 0.007 μM for AChE, IC₅₀ = 0.044 ± 0.004 μM for BuChE), self-induced Aβ aggregation (58.4% ± 2.1% at 20 μM), and MAO-B (IC₅₀ = 0.18 ± 0.01 μM), suggesting that 17d might be an excellent multifunctional agent for AD treatment. In addition, compounds 15a and 15b were identified as selective inhibitors of BuChE at micromolar concentrations. Full article