Introduction: Breast cancer (BC) is a heterogeneous disease involving a network of numerous extracellular signal transduction pathways. The phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (Akt)/mechanistic target of rapamycin (mTOR) pathway is crucial for understanding the BC development. Phosphoinositide 3-kinase, phosphatase and tensin homolog (PTEN), mTOR, Akt, 3-phosphoinositide-dependent kinase 1 (PDK1), FoxO1, glycogen synthase kinase 3 (GSK-3), mouse double minute 2 (MDM2), H-Ras, and proapoptotic B-cell lymphoma 2 (BCL-2) family protein (BAD) proteins are key drivers of this pathway and potential therapeutic targets. Pleurotus ostreatus is an edible mushroom that is rich in flavonoids and phenols that can serve as potential inhibitors of proteins in the PI3K/Akt/mTOR pathway. Aim: This study evaluated the anticancer properties of P ostreatus through a structure-based virtual screening of 22 biologically active compounds present in the mushroom. Method: Model optimization was carried out on PI3K, PTEN, mTOR, Akt, PDK1, FoxO1, GSK-3, MDM2, H-Ras, and BAD proteins in the PI3K/Akt/mTOR pathway and molecular docking of compounds/control inhibitors in the binding pocket were simulated AutoDock Vina in PyRx. The drug likeness, pharmacokinetic, and pharmacodynamic features of prospective docking leads were all anticipated. Result: Several potent inhibitors of the selected key driver proteins in PI3K/Akt/mTOR pathway were identified from P ostreatus. Ellagic acid with binding affinities of −8.0, −8.0, −8.1, −8.2, −6.2, and −7.1 kcal/mol on PI3K, Akt, PDK1, GSK-3, MDM2, and BAD, respectively, had better binding affinity compared with their reference drugs. Likewise, apigenin (−7.8 kcal/mol), chrysin (−7.8 kcal/mol), quercetin (−6.4 kcal/mol), and chlorogenic acid (−6.2 kcal/mol) had better binding affinities to PTEN, mTOR, FoxO1, and H-Ras proteins, respectively. Conclusion: Ellagic acid, apigenin, luteolin, quercetin, chlorogenic acid, chrysin, and naringenin phytochemicals are seen as the better lead molecules due to their ability to strongly bind to the proteins under study in this pathway. Analogs of these compounds can also be designed as potential drugs.

6-Pyruvoyl tetrahydropterin synthase (6-PTPS) is a lyase involved in the synthesis of tetrahydrobiopterin. In Plasmodium species where dihydroneopterin aldolase (DHNA) is absent, it acts in the folate biosynthetic pathway necessary for the growth and survival of the parasite. The 6-pyruvoyl tetrahydropterin synthase of Plasmodium falciparum ( PfPTPS) has been identified as a potential antimalarial drug target. This study identified potential inhibitors of PfPTPS using molecular docking techniques. Molecular docking and virtual screening of 62 compounds including the control to the deposited Protein Data Bank (PDB) structure was carried out using AutoDock Vina in PyRx. Five of the compounds, N,N-dimethyl- N’-[4-oxo-6-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-3H-pteridin-2-yl]methanimidamide (140296439), 2-amino-6-[(1R)-3-cyclohexyl-1-hydroxypropyl]-3H-pteridin-4-one (140296495), 2-(2,3-dihydroxypropyl)-8,9-dihydro-6H-pyrimido[2,1-b]pteridine-7,11-dione (144380406), 2-(dimethylamino)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-hydroxymethyl]-3H-pteridin-4-one (135573878), and [1-acetyloxy-1-(2-methyl-4-oxo-3H-pteridin-6-yl)propan-2-yl] acetate (136075207), showed better binding affinity than the control ligand, biopterin (135449517), and were selected and screened. Three conformers of 140296439 with the binding energy of −7.2, −7.1, and −7.0 kcal/mol along with 140296495 were better than the control at −5.7 kcal/mol. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted good pharmacokinetic properties of all the compounds while reporting a high risk of irritant toxicity in 140296439 and 144380406. The study highlights the five compounds, 140296439, 140296495, 144380406, 135573878 and 136075207, as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development.

Pancreatic lipase is an enzyme crucial for breaking down fats through hydrolysis, and inhibiting it is important for managing obesity. This study evaluated the lipase inhibitory profile of the leaf (SALE) and vine (SAVE) of Secamone afzelii, explored the modes of inhibition, identified the primary compounds responsible for this effect, and examined their molecular interactions with lipase using in vitro and in silico techniques. SALE (IC50: 0.41 ± 0.02 mg/mL) exhibited higher lipase inhibitory activity compared to SAVE (IC50: 0.95 ± 0.05 mg/mL), although it was significantly lower than orlistat (IC50: 0.07 ± 0.00 mg/mL) across all concentrations. S. afzelii extracts inhibited lipase activity through an uncompetitive mode of inhibition. Gas chromatography-mas spectroscopy identified 54 and 47 compounds in SALE and SAVE, respectively, with 9,12-octadecadienoic acid (Z, Z)-, n-hexadecanoic acid and 4S,6R-dimethyl-7R-hydroxynonan-3-one identified as the most abundant compounds in both extracts. The binding energy of the top five ligands from S. afzelii ranged from −7.7 to −6.6 kcal/mol, outperforming that of orlistat (−4.4 kcal/mol). The ligands and orlistat had similar binding poses stabilised by hydrogen and π interactions with CYS299, SER301, CYS304, ASN425 and VAL426. These compounds were predicted to possess promising pharmacokinetic, lipophilic and hydrophilic properties. These results offer insights into the traditional use of S. afzelii for treating obesity and valuable information on potential drug candidates that can be optimised for combating this disease.

The rapid increase of resistance to insecticides among Anopheles mosquitoes, the primary vectors of malaria, highlights the necessity for new approaches in controlling vectors. RNA interference (RNAi) offers a targeted and environmentally safer alternative approach. Arginase in Anopheles gambiae, involved in nitrogen metabolism, presents a compelling target due to its potential role in modulating mosquito immune responses and influencing parasite development and vectorial competency. The study focused on designing and evaluating Dicer-substrate small interfering RNA (DsiRNA) molecules targeting arginase in An. gambiae to disrupt parasite development and reduce malaria transmission. DsiRNAs were designed using Integrated DNA Technologies and optimized based on GC content, secondary structure prediction, thermodynamic parameters, and off-target screening. The derived 21-mer guide strands were further evaluated through molecular docking to assess interactions with An. gambiae Ago2. To validate the docked complex for stability, a molecular dynamics (MD) simulation using 100 ns was performed, revealing stable RMSD trajectories, sustained hydrogen bonding, maintained structural compactness, and minimal residue fluctuation, indicating persistent Ago2-guide strand interactions under physiological conditions. Eight DsiRNAs demonstrated optimal biophysical and specificity profiles, among which DsiRNA6, followed by DsiRNA8, and DsiRNA1 exhibited favorable binding energy and dynamic stability. These findings highlight the structural feasibility and functional potential of selected DsiRNAs as candidates for arginase knockdown in An. gambiae and support RNAi-based strategies as promising alternatives for vector control.

Increasing resistance to insecticides and their accompanying off-target effects call for the development of biodegradable insecticides with selective metabolism-based targets. Anopheles gambiae trehalose-6-phosphate synthase ( Ag TPS), the first enzyme in the trehalose metabolic pathway, is essential for key developmental processes in the organism but absent in vertebrates, making it an attractive insecticidal target. This study aims to evaluate the inhibitory potential of neem-derived compounds against Ag TPS using in silico methods. The 3D structure was predicted, and its active-site residues were identified based on conserved TPS homologues. A library of 275 neem phytochemicals was compiled from IMPPAT and Dr Duke’s databases, alongside known substrates and inhibitors. Molecular docking was performed using AutoDock Vina at the glucose-6-phosphate (G6P), UDP-glucose (UDPG), and combined binding sites. Protein–ligand interactions were analysed using LigPlot+, while insecticide-likeness and ADMET properties were evaluated using QEPest and pkCSM. Several neem-derived compounds exhibited stronger binding affinities to Ag TPS than the natural substrates across all binding sites. Tannic acid showed a high binding affinity across all binding sites, with a range of -11.3 to -12.1 kcal/mol, showing interactions with conserved catalytic residues. Other compounds, including 1-cinnamoylmelianolone, nimbilin, 6-acetylnimbandiol, and 7-deacetyl-7-oxogedunin, also demonstrated strong and consistent binding, frequently outperforming known TPS inhibitors. ADMET analysis revealed that tannic acid possessed unfavourable pharmacokinetic and toxicity profiles. In contrast, limonoids such as 1-cinnamoylmelianolone and nimbilin displayed a more favourable balance between potency, insecticide-likeness, and predicted safety. Neem-derived phytochemicals show significant potential as inhibitors of Ag TPS, supporting Ag TPS as a promising target for selective mosquito control. While tannic acid demonstrates strong binding affinity, its poor drug-likeness limits practical application. The limonoids, such as 1-cinnamoylmelianolone and nimbilin, thus emerge as more viable lead candidates. These findings provide molecular insights into neem’s insecticidal activity and support further experimental validation for vector control applications.