Neurodegenerative diseases, for example Alzheimer’s, are perceived as driven by hereditary, cellular, and multifaceted biochemical actions. Numerous plant products, for example flavonoids, are documented in studies for having the ability to pass the blood-brain barrier and moderate the development of such illnesses. Computer-aided drug design (CADD) has achieved importance in the drug discovery world; innovative developments in the aspects of structure identification and characterization, bio-computational science, and molecular biology have added to the preparation of new medications towards these ailments. In this study we evaluated nine flavonoid compounds identified from three medicinal plants, namely T. diversifolia, B. sapida, and I. gabonensis for their inhibitory role on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activity, using pharmacophore modeling, auto-QSAR prediction, and molecular studies, in comparison with standard drugs. The results indicated that the pharmacophore models produced from structures of AChE, BChE and MAO could identify the active compounds, with a recuperation rate of the actives found near 100% in the complete ranked decoy database. Moreso, the robustness of the virtual screening method was accessed by well-established methods including enrichment factor (EF), receiver operating characteristic curve (ROC), Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC), and area under accumulation curve (AUAC). Most notably, the compounds’ pIC₅₀ values were predicted by a machine learning-based model generated by the AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best models achieved for AChE, BChE and MAO were models kpls_radial_17 (R² = 0.86 and Q² = 0.73), pls_38 (R² = 0.77 and Q² = 0.72), kpls_desc_44 (R² = 0.81 and Q² = 0.81) and these externally validated models were utilized to predict the bioactivities of the lead compounds. The binding affinity results of the ligands against the three selected targets revealed that luteolin displayed the highest affinity score of −9.60 kcal/mol, closely followed by apigenin and ellagic acid with docking scores of −9.60 and −9.53 kcal/mol, respectively. The least binding affinity was attained by gallic acid (−6.30 kcal/mol). The docking scores of our standards were −10.40 and −7.93 kcal/mol for donepezil and galanthamine, respectively. The toxicity prediction revealed that none of the flavonoids presented toxicity and they all had good absorption parameters for the analyzed targets. Hence, these compounds can be considered as likely leads for drug improvement against the same.

Uterine fibroids (UF) are reproductive conditions that occur as tumours in the womb. It is a gynecological outgrowth of diverse sizes often allied with infertility risks that might require surgery to reduce the complication in the worst-case scenario in women. Recent studies have uncovered that estrogen can induce and facilitate other target pathways' action on target cells for UF's pathogenesis, among the targets probed for pharmaceutical intervention. This study screens the interaction effects of 32 phytochemicals from indigenous and adopted potent Chinese plants and herbs; Chamomile, Pomegranate, Red clover, Cinnamomum, and Date palm, against estrogen receptor alpha (ESRα) to serve for anti-UF drug candidates using in silico tools through the molecular mechanisms. The interaction identifies coumestrol as the best-docked candidate (-9.6 kcal/mol) with a correlation to the binding free energy (-30.487 kcal/mol) as compared to the standard drug tamoxifen (-9.3 kcal/mol; -46.928 kcal/mol). The downstream post-docking evaluation reveals coumestrol to have excellent pharmacokinetics, drug-likeness, leadlikeness (no violation), less toxic (LD50; 2991 mg/kg), and highly interactive with ESRα. Coumestrol was top-ranked for ESRα (1QKU) target by PharmMapper among 300 human protein targets, with a z-score of 1.19368. The density functional theory (DFT) and dynamic simulation of 200 ns reveal regions of coumestrol structure and its complex that contribute to the chemical reactivity, stability, flexibility, and compactness of druggability. Ultimately, coumestrol emerged as a potential candidate suitable for anti-UF management, therefore future direction for its application should be on the design and synthesis of new structural derivatives for further in silico, in vitro, and in vivo studies.

The gene expression of serotonin 5-hydroxytryptamine receptor 3A (receptor 3A:HTR3A) as well as the concentration of electrolytes in male Wistar rats after administration of graded doses of marijuana extract was investigated. Twelve groups (3 control and 9 test groups) of 6 animals each were daily exposed to 12.5, 25 and 50 mg/kg b.w doses of petroleum ether extract of marijuana for 4, 8 and 12 weeks. The expressions of the gene were obtained using reverse transcriptase-polymerase chain reaction (RT-PCR) while electrolytes concentrations were determined. An upregulation of over 90% was observed in the expression of HTR3A after exposure to the highest dose throughout the exposure period. There was significant increase in the plasma potassium concentration at all doses while there was a decrease in the brain only at 50 mg/kg dose throughout the exposure period. Sodium concentration in the brain was not affected by the doses over the period of exposure but plasma concentration decreased significantly. All the doses of marijuana extract significantly increased calcium concentration in the brain after prolonged exposure but the plasma concentration remained unchanged. This suggests that different doses of marijuana extract alter the expression of serotonin receptor and electrolyte concentrations over a period of time with possible neurological consequences.

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a promising drug target for the development of diabetes medications via an inhibition mechanism. Using a computational approach, this study investigates the binding mechanism of lead optimized natural compounds from Allium sativum against the human PTP1B. The molecular docking, induced-fit docking, and binding free energy calculations were analyzed using Schrödinger Suite 2021-2. MD simulation, and gene enrichment analysis was achieved via the Desmond module of Schrödinger to identify best compounds as inhibitors against PTP1B in diabetes management. The docking scores of the lead optimized compounds were good; 5280443_121 from apigenin had the best binding score of -9.345 kcal/mol, followed by 5280443_129 with a binding score of -9.200 kcal/mol, and 5280863_177 from kaempferol had a binding score of -8.528 kcal/mol, followed by 5280863_462 with a binding score of -8.338 kcal/mol. The top two lead optimized compounds, docked better than the standard PTP1B inhibitor (-7.155 kcal/mol), suggesting them as potent inhibitors than the standard PTP1B inhibitor. The outcomes of the induced-fit docking were consistent with the increased binding affinity used in the Glide computation of the five conformed poses between the derivatives (5280443_121, 5280443_129, 5280863_177, and 5280863_462) and the protein (PTP1B). Based on the binding fee energies (MM-GBSA), the lead optimized compounds from kaempferol exhibited more stability than those from apigenin. In the pharmacophore development, all the models exhibit good results across the different metrics. The best performing model with five of five matches on a 1.34 and 1.33 phase score was DDRRR_1, DDRRR_2, and DDDRR_1. The average BEDROC value (= 160.9) was 1, while the average EF 1% value across all models was 101. There were no substantial conformational modifications during the MD simulation process, indicating that the apigenin derivatives (5280443_121) was stable in the protein's active site in 100 ns. IGF1R, EGFR, INSR, PTPN1, SRC, JAK2, GRB2, BCAR1, and IRS1 are among the 11 potential targets found in the protein-protein interaction (PPI) of A. sativum against PTP1B that may be important in A. sativum's defense against PTP1B. Sixty-four (64) pathways were found by KEGG pathway enrichment analysis to be potentially involved in the anti-PTP1B of A. sativum. Consequently, data obtained indicates the effectiveness of the in silico studies in identifying potential lead compounds in A. sativum against PTP1B target.Communicated by Ramaswamy H. Sarma.

This study aimed to examine the therapeutic activity of the cinnamic acid derivative KAD-7 (N′-(2,4-dichlorobenzylidene)-3-(4-methoxyphenyl) acrylohydrazide) on Fe²⁺-induced oxidative hepatic injury via experimental and computational models. In addition, the role of ATPase and ectonucleoside triphosphate diphosphohydrolase (ENTPDase) in the coordination of cellular signals is speculated upon to proffer suitable therapeutics for metabolic stress disorder upon their inhibition. While we know little about therapeutics with flexible dual inhibitors for these protein targets, this study was designed to screen KAD-7’s (N′-(2,4-dichlorobenzylidene)-3-(4-methoxyphenyl) acrylohydrazide) inhibitory potential for both protein targets. We induced oxidative hepatic damage via the incubation of hepatic tissue supernatant with 0.1 mM FeSO₄ for 30 min at 37 °C. We achieved the treatment by incubating the hepatic tissues with KAD-7 under the same conditions. The catalase (CAT), glutathione (GSH), malondialdehyde (MDA), ATPase, and ENTPDase activity were all measured in the tissues. We predicted how the drug candidate would work against ATPase and ENTPDase targets using molecular methods. When hepatic injury was induced, there was a significant decrease in the levels of the GSH, CAT, and ENTPDase (p < 0.05) activities. In contrast, we found a noticeable rise in the MDA levels and ATPase activity. KAD-7 therapy resulted in lower levels of these activities overall (p < 0.05), as compared to the control levels. We found the compound to have a strong affinity for ATPase (−7.1 kcal/mol) and ENTPDase (−7.4 kcal/mol), and a better chemical reactivity than quercetin. It also met all drug-likeness parameters. Our study shows that KAD-7 can protect the liver from damage caused by FeSO₄ by reducing oxidative stress and purinergic actions. Our studies indicate that KAD-7 could be developed as a therapeutic option since it can flexibly inhibit both ATPase and ENTPDase.