Drugs and Drug Candidates

Background: Type 2 diabetes mellitus (T2DM) is a complex metabolic disease requiring multi-targeted therapeutic strategies. Gunnera perpensa and Erythrina zeyheri are traditionally used in diabetes management, but their mechanisms remain poorly understood. Methods: This study used in vitro, metabolomics, and network pharmacology approaches to elucidate their antidiabetic potential. Leaf extracts were screened for glucose utilization in C2C12 cells, and cytotoxicity in Vero cells. Metabolites profiled via GC×GC-TOF-MS and those retrieved from Phytochemical Interaction Database were evaluated for drug-likeness and target prediction using SwissADME and SwissTargetPrediction. Diabetes-related targets were obtained from databases, and overlapping targets were used to construct interaction networks using Cytoscape and STRING. Functional enrichment analyses were conducted via DAVID for GO and KEGG pathways. Results: G. perpensa acetone and methanol extracts enhanced superior glucose utilization (IC₅₀ = 78.5 and 94.8 µg/mL, respectively), with low cytotoxicity (LC₅₀ > 600 µg/mL). Key compounds including arabinose, identified from both plants, showed multi-target binding potential against STAT3, PIK3RI and JAK2. Enrichment analyses revealed pathways related to insulin signaling, inflammation, and glucose metabolism. Conclusions: This study supports the therapeutic relevance of phytochemical synergy in the traditional use of both plants and demonstrated systems-level approaches for elucidating complex drug–target interactions in T2DM. Full article

Background/Objectives: Molnupiravir (MOV) and nirmatrelvir (NMV) are antiviral drugs that were FDA-approved under the emergency use authorization (EUA) for coronavirus disease-2019 (COVID-19) treatment. MOV and NMV target the viral RNA-dependent RNA polymerase and main protease, respectively. Paxlovid is a combination of NMV and ritonavir (RTV), an inhibitor of the human cytochrome P450-3A4 (hCYP3A4). In this study, the structural consequences in the hCYP3A4 caused by MOV-induced mutations (MIM) were evaluated using in silico tools. Methods: MOV-induced mutations (MIM) were inserted into all the possible hotspots in the active site region of the hCYP3A4 gene, and mutant protein models were built. Structural changes in the heme-porphyrin ring of hCYP3A4 were analyzed in the presence and absence of substrates/inhibitors, including RTV. Molecular dynamics (MD) simulations were performed to analyze the effect of MIM-induced structural changes in hCYP3A4 on drug binding. Results: MD simulations confirm that MIMs, R375G and R440G in hCYP3A4 severely affect the heme-porphyrin ring stability by causing a tilt that in turn affects RTV binding, suggesting a possible inefficiency in the function of hCYP3A4. Similar results were seen for amlodipine, atorvastatin, sildenafil and warfarin, which are substrates of hCYP3A4. Conclusions: The current in silico studies indicate that hCYP3A4 containing MIMs can create complications in the treatment of COVID-19 patients, particularly with co-morbidities due to its functional inefficiency. Hence, clinicians must be vigilant when using MOV in combination with other drugs. Further in vitro studies focused on hCYP3A4 containing MIMs are currently in progress to support our current in silico findings. Full article

Background/Objectives: Despite continuous pharmacological advances, the treatment of schizophrenia remains challenging, and suboptimal outcomes are still too frequent. There are currently limited new approved drugs without resistance. Methods: For this reason, drug repurposing presents a promising solution for identifying existing drugs with therapeutic effects for schizophrenia. In this study, we provide a workflow of signature-based drug repurposing methodology. We initially utilized a dataset from Gene Expression Omnibus which consists of RNA sequence data from blood-derived leukocyte samples from individuals with schizophrenia and control subjects, and conducted an analysis. Results: This analysis identified 1205 statistically significant differentially expressed genes, of which 150 upregulated and 150 downregulated genes were used in the CMap and L1000CDS2 tools. Then, each database generated a list of potential compounds that could reverse the disease’s signature and potentially have therapeutic effects for schizophrenia. Subsequently, the compounds associated with the disease, as identified in the research, were chemically clustered, and then their modes of action were predicted. In the last stage, we conducted a literature review to evaluate the relationship of these modes of action with the disease. Conclusions: This systematic analysis provided a list of potential drugs for schizophrenia treatment so that their efficacy can be evaluated in the wet-lab experiments, which is the next stage of drug repurposing. Full article

This paper does not describe the results of a systematic search for the mechanism of action of cyclophosphamide and the consequences and possible indications arising from this mechanism. Rather, it describes a puzzle in which our own results, with some of them being very old, were re-evaluated with the latest biochemical knowledge and supplemented by results from the scientific literature. The mechanism of action of cyclophosphamide, which has been indispensable in clinical practice for 60 years, was unknown until recently simply because biochemical knowledge was lacking and because results from in vitro experiments were uncritically extrapolated to in vivo conditions. In vitro, the DNA alkylating metabolite phosphoramide mustard (PAM) is formed from the CP metabolite aldophosphamide (ALD) by phosphate and bicarbonate ion-catalyzed β-elimination of acrolein; in vivo, however, ALD is cleaved by phosphoesterases or DNA polymerase δ and ε, which are associated with 3′-5′ exonucleases, into the complementary metabolites PAM and 3-hydroxypropanal (HPA). The following describes the mechanism of action of CP, namely the complementary interaction of alkylating PAM and apoptosis-enhancing HPA, and it is shown that by optimizing the complementary effects of PAM and HPA, the antitumor efficacy in the P388 mouse tumor model can be increased by more than ten thousand-fold. Further experiments show that by optimizing the interaction of DNA alkylation and enhancing the resulting apoptosis by HPA, the formation of resistant metastases can be prevented and low-toxicity chemotherapy can be achieved. Full article

Background/Objectives: We have established a robust, cell-based high-throughput screening platform capable of identifying SARS-CoV-2 entry inhibitors within a BSL-2 facility. Methods: Using a curated compound library, we conducted a screening campaign that led to the discovery of potent viral entry inhibitors active in both pseudoviral and infectious SARS-CoV-2 inhibition assays. Results: Among those, Hit-1 exhibited submicromolar antiviral activity across all tested SARS-CoV-2 strains, including the highly transmissible Omicron subvariants. Biophysical binding assays confirmed that Hit-1 and related compounds directly engage the prefusion-stabilized SARS-CoV-2 spike proteins of both authentic WA1/2020 and Omicron viral strains. To elucidate potential binding orientations and interactions of the hit compounds with the SARS-CoV-2 spike protein, molecular docking studies were performed targeting two putative binding sites. Conclusions: Preliminary structure–activity relationship studies identified a promising subset of drug-like 7,8-dihydropyrido[4,3-d]pyrimidine-based inhibitors with potential for further development as novel therapeutic agents aimed at blocking viral entry and thereby preventing or mitigating SARS-CoV-2 infection. Among these, compound 13 stands out due to its superior in vitro potency and favorable pharmacokinetic properties, positioning it as a strong candidate for in vivo efficacy evaluation. Full article

Background/Objectives: This study investigated the flavonoid enrichment and antimicrobial activity of the ethyl acetate fraction (EAF) obtained from Croton blanchetianus (Euphorbiaceae) leaves against Staphylococcus aureus, including the methicillin-resistant strains (MRSA) that were isolated, as well as its possible mechanism of action. Methods: Croton blanchetianus leaves were extracted with ethanol:water (50%), then the extract was spray-dried and partitioned (8×) with ethyl acetate. Phytochemical analysis was performed using thin layer chromatography (TLC), while antibacterial activity was conducted using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods. Results: Chemical profiling (TLC) confirmed multiple flavonoid bands and the presence of hyperoside; the total flavonoid content in the EAF reached 25.3% (≈2.28× the spray-dried extract and 6.65× the aqueous fraction). The MIC and MBC assays against S. aureus ATCC 29213 and six clinical isolates showed an MIC of 4–32 μg/mL and an MBC of 16–64 μg/mL for EAF. The combination of EAF with chloramphenicol showed a complete synergistic effect for S. aureus ATCC 29213 and S. aureus UFPEDA 705, a partial effect for S. aureus UFPEDA-659 and S. aureus UFPEDA-671, antagonistic effect for S. aureus UFPEDA 731 and S. aureus UFPEDA 802, and no effect for S. aureus UFPEDA-691. Growth curves indicated time- and concentration-dependent inhibition. Membrane integrity assays revealed K⁺ efflux and release of DNA/RNA and proteins, suggesting bacterial membrane destabilization as a likely mechanism. Conclusions: The flavonoid-rich fraction of C. blanchetianus exhibits potent anti-S. aureus activity, including MRSA. Furthermore, it was observed that EAF has a synergistic effect with chloramphenicol and acts through membrane damage, making it a candidate for a phytoderived adjuvant in antimicrobial therapies. Full article

Background/Objectives: Natural products, especially plant metabolites, play a crucial role in drug development and are widely used in medicine, cosmetics, and nutrition. The present review aims to provide a comprehensive overview of the pharmacological profile of Glycyrrhizin (GL), with a specific focus on its molecular targets. Methods: Scientific literature was thoroughly retrieved from reputable databases, including Scopus, Web of Science, and PubMed, up to 30 July 2025. The keywords “glycyrrhizin” and “glycyrrhizic acid” were used to identify relevant references, with a focus on pharmacological applications. Studies on synthetic analogs, non-English publications, non-pharmacological applications, and GL containing crude extracts were largely excluded. Results: Glycyrrhizin, the major bioactive constituent of Glycyrrhiza glabra, exhibits diverse pharmacological activities, including anti-inflammatory, antiviral, hepatoprotective, antitumor, neuroprotective, and immunomodulatory effects. These actions are primarily mediated through the inhibition of high-mobility group box 1 (HMGB1) and the modulation of key signaling pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and various cytokine networks. As a result of its therapeutic potential, GL-based formulations, including Stronger Neo-Minophagen C, and GL-rich extracts of G. glabra are commercially available as pharmaceutical preparations and food additives. Conclusions: Despite its therapeutic potential, the clinical application of GL is limited by poor oral bioavailability, metabolic variability, and adverse effects such as pseudoaldosteronism. Hence, careful consideration of pharmacokinetics and safety is essential for translating its therapeutic potential into clinical practice. Full article

Background/Objectives: Human Herpes Simplex Virus 1 (HSV-1) is a common pathogen that establishes lifelong latent infections. The emergence of drug resistance necessitates novel therapeutic strategies. This study introduces a novel antiviral approach: a bivalent degrader designed to induce the degradation of an essential protein. Methods: A structural model of ICP0, generated via the Chai-1 AI platform, was analyzed with fpocket, P2Rank, and KVFinder to identify a superior allosteric target site. An iterative de novo design workflow with CReM-dock then yielded a lead scaffold based on its predicted affinity and drug-like properties. This selected “warhead” was used to rationally design the final bivalent degrader, ICP0-deg-01, for the ICP0 dimer model. Results: The generative process yielded a lead chemical scaffold that was selected based on its predicted binding affinity and favorable drug-like properties. This scaffold was used to rationally design a single candidate bivalent degrader, ICP0-deg-01. Our structural model predicts that ICP0-deg-01 can successfully bridge two ICP0 protomers, forming an energetically favorable ternary complex. Conclusions: This work provides a computational proof-of-concept for a novel class of anti-herpetic agents and identifies a lead candidate for future molecular dynamics simulations and experimental validation. Full article

Background/Objectives: Malaria is a prominent vector-borne disease, with a high mortality rate, particularly in children under five years old. Despite the use of various insecticides for its control, the emergence of resistant mosquitoes poses a significant public health threat. Acetylcholinesterase (AChE) is a crucial enzyme in nerve transmission and a primary target for insecticide development due to its role in preventing repeated nerve impulses. Recent studies have identified difluoromethyl ketone (DFK) as a potent inhibitor of both sensitive and resistant Anopheles gambiae acetylcholinesterase (AgAChE). This study aimed to identify novel AgAChE inhibitors that could be explored for malaria prevention. Methods: We performed a virtual screening on the PubChem database using a pharmacophore model from difluoromethyl ketone-inhibited AgAChE’s crystal structure. The most promising compound was then subjected to molecular docking and dynamics studies with AgAChE to confirm initial findings. ADMET and agrochemical likeness (ag-like) properties were also analyzed to assess its potential as an agrochemical agent. Results: PubChem18463786 was identified as the most suitable compound from the virtual screening. Molecular docking and molecular dynamics studies confirmed its strong interaction with AgAChE. The ADMET and ag-like analyses indicated that PubChem18463786 possesses physicochemical properties suggesting a high probability of non-absorption in humans and meets the criteria for agrochemical similarity. Conclusions: Our findings suggest that PubChem18463786 is a potential AgAChE inhibitor candidate. After validation through in vitro and in vivo experiments, it could be exploited for malaria prevention and serve as a lead compound for the synthesis of new, more effective, and selective agrochemical agents. Full article

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies. Full article

Background: Based on our previously reported series of novel 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives, we have now designed, synthesized, and tested a new series of novel restricted and simplified structural analogues of these compounds against Plasmodium falciparum in vitro; i.e., the 1,3-bis[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3-bis[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds. Methods & Results: The pharmacological results revealed significant antimalarial activity, with IC₅₀ values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new nitrogen-containing polyphenyl- or -phenoxymethylbenzene compounds was evaluated on human HepG2 cells. The compound 1f, the 1,3-bis[(4-(3-(morpholin-1-yl)propyl)aminomethyl)phenoxy)methyl]benzene derivative, emerged as one of the most potent and promising antimalarial candidates, demonstrating a cytotoxicity/antiprotozoal activity ratio of 594 against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. Additionally, the 1,3-bis[((substituted aminomethyl)phenyl)methyl]benzene compound 1j and the 1,3-bis[((substituted aminomethyl)phenoxy)methyl]benzenes 2p and 2q also showed strong antimalarial potential, with selectivity indexes (SI) of over 303, 280, and 217, respectively, against the 3D7 strain, which has mefloquine-reduced sensitivity. Furthermore, the 1,3-bis[(4-(pyridin-2-ylethylaminomethyl)phenyl)methyl]benzene 2k was identified as the most noteworthy antimalarial compound, exhibiting a selectivity index (SI) that was superior to 178 against the chloroquine-resistant Plasmodium falciparum W2 strain. It has previously been suggested that the telomeres of P. falciparum may serve as potential targets for these polyaromatic compounds; thus, we assessed the ability of our novel derivatives to stabilize parasitic telomeric G-quadruplexes using a FRET melting assay. Conclusions: However, regarding the stabilization of the protozoan G-quadruplex, it was noted that the few substituted derivatives, which showed interesting stabilization profiles, were not necessarily the most effective antimalarial compounds against both Plasmodium strains. Moreover, these new compounds did not show promising stabilizing effects on the different G4 sequences. Therefore, no correlation arises between their antimalarial activity and the selectivity of their binding to G-quadruplexes. Full article

Background: Drug development for leishmaniases treatment follows a very selective process in order to propose drug candidates that possess all the qualities that meet the strict specifications of the pharmaceutical industry. Drug resistance is a limiting factor that can impact the lifespan of a marketed drug. It is now essential that the risk of drug resistance be evaluated at the early stage of in vitro studies to discard a lead compound that could quickly generate drug resistance once available on the market. Objectives: This article aims to estimate the risk of drug resistance emergence for a promising drug candidate at the in vitro early stage of drug development. Methods: A sequential method is proposed to study some of the phenotypic characteristics and parameters of resistant parasites such as time to achieve maximal resistance during stepwise drug pressure, resistance amplitude, stability, fitness, and infectivity both in vitro and in vivo. Results: Some examples with drugs in clinical use and former drug candidates are given. Conclusions: This method providing an evaluation of the risk of drug resistance from an in vitro model of Leishmania donovani be extrapolated to other Leishmania species. Full article

The kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders. Full article

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder primarily targeting joints, leading to pain, swelling, and stiffness. RA results from the body’s own immune system attacking its own tissues. Currently, there are various treatments available for RA including disease-modifying antirheumatic drugs (DMARDs) and NSAIDs. Leflunomide (LEF) is a USFDA-approved synthetic DMARD which is being widely prescribed for the management of RA; however, it faces several challenges such as prolonged drug elimination, hepatotoxicity, and others. LEF exerts its therapeutic effects by inhibiting dihydroorotate dehydrogenase (DHODH), thereby suppressing pyrimidine synthesis and modulating immune responses. Emerging nanotechnology-based therapies help in encountering the current challenges faced in LEF delivery to RA patients. This review enlists the LEF’s pharmacokinetics, mechanism of action, and clinical efficacy in RA management. A comparative analysis with methotrexate, biologics, and other targeted therapies, highlighting its role in monotherapy and combination regimens and the safety concerns, including hepatotoxicity, gastrointestinal effects, and teratogenicity, is discussed alongside recommended monitoring strategies. Additionally, emerging trends in novel formulations and drug delivery approaches are explored to enhance efficacy and minimize adverse effects. Overall, LEF remains a perfect remedy for RA patients, specifically individuals contraindicated with drugs like methotrexate. The therapeutic applicability of LEF could be enhanced by developing more customized treatments and advanced drug delivery approaches. Full article

Background: Hypertension is a serious global health issue affecting over one billion adults and leading to severe complications if left unmanaged. Despite medical advancements, only a fraction of patients effectively have their hypertension under control. Among the factors that hinder adherence to hypertensive drugs are the debilitating side effects of the drugs. The lack of adherence results in poorer patient outcomes as patients opt to live with their condition, instead of having to deal with the side effects. Hence, there is a need to discover new hypertension drug molecules with better side effects to increase patient treatment options. To this end, computational methods such as artificial intelligence (AI) have become an exciting option for modern drug discovery. AI-based computational drug discovery methods generate numerous new lead antihypertensive drug molecules. However, predicting their potential side effects remains a significant challenge because of the complexity of biological interactions and limited data on these molecules. Methods: This paper presents a machine learning approach to predict the potential side effects of computationally synthesised antihypertensive drug molecules based on their molecular properties, particularly functional groups. We curated a dataset combining information from the SIDER 4.1 and ChEMBL databases, enriched with molecular descriptors (logP, PSA, HBD, HBA) using RDKit. Results: Gradient Boosting gave the most stable generalisation, with a weighted F1 of 0.80, and AUC-ROC of 0.62 on the independent test set. SHAP analysis over the cross-validation folds showed polar surface area and logP contributing the largest global impact, followed by hydrogen bond counts. Conclusions: Functional group patterns, augmented with key ADMET descriptors, offer a first-pass screen for identifying side-effect risks in AI-designed antihypertensive leads. Full article

Background/Objective: Cerivastatin (Cer), a cholesterol-lowering statin, was withdrawn from the market due to fatal cases of rhabdomyolysis, particularly when co-administered with gemfibrozil (Gem), a strong CYP2C8 inhibitor. However, the pharmacokinetic (PK) mechanisms underlying these adverse events remain unclear. This study investigates the impact of drug–drug interactions (DDIs) involving Gem and itraconazole (Itr), a potent CYP3A4 inhibitor, on plasma concentrations of Cer and its major metabolites—M23, M1, and cerivastatin lactone (Cer-L)—with a focus on the risk of excessive Cer-L accumulation. Methods: We applied a newly developed Metabolite-Linked Model that simultaneously characterizes parent drug and metabolite kinetics by estimating metabolite formation fractions (f_M) and elimination rate constants (K_eM). The model was calibrated using observed DDI data from Cer + Gem and Cer + Itr scenarios and then used to predict outcomes in an untested Cer + Gem + Itr combination. Results: The model accurately reproduced observed metabolite profiles in single-inhibitor DDIs. Predicted AUCR values for Cer-L were 4.2 (Cer + Gem) and 2.1 (Cer + Itr), with reduced K_eM indicating CYP2C8 and CYP3A4 as primary elimination pathways. In the dual-inhibitor scenario, Cer-L AUCR reached ~70—far exceeding that of the parent drug—suggesting severe clearance impairment and toxic accumulation. Conclusions: Dual inhibition of CYP2C8 and CYP3A4 may cause dangerously elevated Cer-L levels, contributing to Cer-associated rhabdomyolysis. This modeling approach offers a powerful framework for evaluating DDI risks involving active or toxic metabolites, supporting safer drug development and regulatory assessment. Full article

Background/Objectives: Severe malaria, mainly caused by Plasmodium falciparum, remains a significant therapeutic challenge due to increasing drug resistance and adverse effects. Flavonoids, known for their wide range of bioactivities, offer a promising route for antimalarial drug discovery. The aim of this study was to elucidate key structural features associated with antimalarial activity in flavonoids and to develop accurate, interpretable predictive models. Methods: Curated databases of flavonoid structures and their activity against P. falciparum strains and enzymes were constructed. Molecular fingerprinting and decision tree analyses were used to identify key pharmacophoric groups. Subsequently, molecular descriptors were generated and reduced to build multiple classification and regression models. Results: These models demonstrated high predictive accuracy, with test set accuracies ranging from 92.85% to 100%, and R² values from 0.64 to 0.97. Virtual screening identified novel flavonoid candidates with potential inhibitory activity. These were further evaluated using molecular docking and molecular dynamics simulations to assess binding affinity and stability with Plasmodium proteins (FabG, FabZ, and FabI). The predicted active ligands exhibited stable pharmacophore interactions with key protein residues, providing insights into binding mechanisms. Conclusions: This study provides highly predictive models for antimalarial flavonoids and enhances the understanding of structure–activity relationships, offering a strong foundation for further experimental validation. Full article