Mercy Bella-Omunagbe

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.

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.

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.

Context: Prostate cancer remains a significant global health concern, and understanding the molecular drivers of this disease is crucial for developing effective diagnostic and therapeutic strategies. Steroid receptor coactivator-3 (SRC-3), a member of the SRC family, has emerged as a key player in prostate cancer pathogenesis. Aims: To examine the role of SRC-3 in prostate cancer, encompassing molecular mechanisms, clinical implications, and therapeutic opportunities. Methods: A systematic literature search following PRISMA guidelines was conducted in PubMed, PMC, and other relevant databases to identify studies that investigate SRC-3 in prostate cancer. Results: 785 articles were retrieved from databases using specific keywords and MeSH terms related to SRC-3 and Prostate Cancer. After removing 461 duplicates, 260 articles were excluded based on title and abstract review. Subsequently, a comprehensive screening by three researchers resulted in 47 relevant articles for this systematic review. Evidence suggests that SRC-3 expression correlates with prostate cancer aggressiveness, disease recurrence, and poor patient outcomes. Its potential as a diagnostic biomarker and therapeutic target if explored, offers insights into personalized medicine approaches. Conclusions: SRC-3 plays a pivotal role in prostate cancer, influencing disease progression and clinical outcomes. Understanding the molecular intricacies of SRC-3 in prostate cancer offers new opportunities for precision medicine and innovative therapeutic approaches. This review provides a comprehensive overview of SRC-3's involvement in prostate cancer, emphasizing its clinical relevance and potential as a therapeutic target, ultimately contributing to improved patient care in the era of personalized oncology.

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.