Excessive exposure to monosodium glutamate (MSG) induces glutamate-mediated excitotoxicity, oxidative stress, and neuroinflammation, culminating in neurobehavioral impairments. Bromelain, a cysteine protease derived from Ananas comosus, exhibits potent antioxidative and anti-inflammatory properties; however, its potential to attenuate excitotoxic neuronal injury remains insufficiently characterized. This study investigated the neuroprotective effects of bromelain against MSG-induced neurotoxicity through integrated behavioral, biochemical, histological, and computational analyses. Male Swiss mice (7-8 weeks) received MSG (4 g/kg, i.p.) to induce excitotoxicity and were subsequently treated orally with bromelain (50 or 100 mg/kg) or fluoxetine (1 mg/kg) for 21 days. Behavioral tests assessed locomotor, cognitive, and affective functions, while biochemical and histological analyses evaluated oxidative stress, neuroinflammatory markers, and neurotransmitter-modulating enzyme activities. In silico AlphaFold3 modeling and protein-protein docking were employed to elucidate bromelain's interactions with acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), and glutamate decarboxylase (GAD). Bromelain treatment significantly ameliorated MSG-induced behavioral deficits, restored cortical and hippocampal redox balance, suppressed pro-inflammatory cytokines, and preserved neuronal cytoarchitecture. It normalized neurotransmitter metabolism by inhibiting AChE and MAO-B activities while enhancing GAD function. AlphaFold3 modeling revealed a compact, high-confidence bromelain conformation (pLDDT >90) with strong predicted binding affinities to catalytically active residues of AChE, MAO-B, and GAD, supporting its multi-target neuromodulatory role. Altogether, these findings provide the first integrated experimental and computational evidence that bromelain confers neuroprotection by regulating redox homeostasis, inflammation, and neurotransmitter signaling, highlighting its promise as a nutraceutical candidate for mitigating glutamate-mediated neurodegenerative disorders.

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a validated therapeutic target for type 2 diabetes mellitus due to its role in local regeneration of active glucocorticoids. Current inhibitors are often limited by their constrained chemical diversity, moderate potency, and off-target effects. The therapeutic potential of steroidal pregnanes in diabetes and metabolic disorders is widely reported; however, their molecular targets, particularly in glucocorticoid signaling, remain poorly understood. This study explored the interactions of a curated library of steroidal pregnanes with 11β-HSD1 using integrated Machine Learning (ML)-based QSAR, molecular docking, 100 ns Molecular Dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Initial exploratory chemical space analysis of the IC50 bioactivity dataset revealed that hydrogen donors, molecular weight, and lipophilicity may contribute to the bioactivity of 11β-HSD1 inhibitors. Evaluation of 42 ML algorithms based on performance metrics revealed Random Forest Regressor (RFR) as a top model for bioactivity predictions. Molecular docking simulation of the top RFR-predicted compounds (pIC50 ≥ 6.0 and pKi ≥ 7.8) with the active site of 11β-HSD1 identified three compounds (pregnane-3, 20-diol disulphate (P1), 20-Piperidin-2-yl-5α-pregnan-3β,20-diol (P2), and 12,20-di-O-benzoyl-pregnane-3β,12β,14β,20-tetraol (P3)). While the reference carbenoxolone primarily involved peripheral polar contacts to stabilize its orientation, the pregnane scaffolds demonstrated deeper insertion into the hydrophobic catalytic cavity of 11β-HSD1, resulting in enhanced shape complementarity and van der Waals packing. The thermodynamic parameters computed from the MD simulation trajectories revealed both the structural stability and intrinsic conformational flexibility of the 11β-HSD1-pregnane complexes. Moreover, the lower MM-GBSA binding energies of P1 (-43.58 kcal/mol) and P3 (-44.95 kcal/mol) as compared with the reference carbenoxolone (-24.19 kcal/mol) indicate high binding affinity and validate the docking scores of the hits. Additionally, the leads exhibited favorable physicochemical and pharmacokinetic profiles. Overall, our findings provide mechanistic insights into ligand binding and highlight key structural features that may account for 11β-HSD1 modulation by steroidal pregnanes, offering a framework for the rational design of pregnane-derived therapeutics.

D-ribose-L-cysteine (DRc) has been shown to protect against copper-induced neurotoxicity. However, its potential protective effect against copper-induced testicular toxicity has not been previously investigated. The present study aimed to evaluate the protective efficacy of DRc against copper-induced gonadotoxicity and to elucidate the underlying mechanisms using complementary in vivo and in silico approaches. Male Swiss mice were administered oral treatments of copper sulfate [CuSO4 (100 mg/kg)] and/or DRc (10, 25, and 50 mg/kg) once a day for 28 days. After euthanization, the epididymal sperm were immediately subjected to semen analysis, and the excised testicular tissues were processed for biochemical and histomorphological assays. In parallel, network pharmacology analysis was performed to predict key molecular targets and pathways associated with DRc-mediated gonadoprotection. DRc significantly improved copper-induced reproductive toxicity, as evidenced by improvements in sperm count, motility, viability, morphology, gonadosomatic index, testosterone levels, and testicular histoarchitecture. These protective effects were accompanied by a marked reduction in oxidative stress (decreased levels of MDA and NO, and increased levels of GSH and SOD), inflammation (e.g., decreased IL-6 and TNF-α), and apoptosis (e.g., decreased caspase-3). Network pharmacology analysis identified 19 targets, including caspase-3 (CasP3), X-linked inhibitor of apoptosis protein (XIAP), nitric oxide synthase 1 (NOS1), Janus kinase 2 (JAK2), and DNA repair protein (RAD50), suggesting coordinated regulation of oxidative stress, inflammatory, apoptotic, and DNA repair pathways. Taken together, DRc mitigates copper-induced gonadotoxicity through modulation of oxidative-inflammatory, apoptotic, and DNA repair machinery.

Myeloid cell leukemia-1 (MCL-1) is a prominent representative of the BCL-2 antiapoptotic protein family and plays a key role in the dysregulation of programmed cell death. Overexpression of MCL-1 has emerged as a survival and drug resistance mechanism in several malignancies. Currently, there’s no FDA-approved MCL-1 inhibitor in clinical use. Herein, we used drug repurposing to address this unmet therapeutic need. We employed a virtual computing technique to screen a customized library of thirty-one antiviral drugs for potential antagonistic activity against MCL-1. We investigated the dynamic interaction of the hits in the MCL-1 binding pocket using molecular dynamics simulation (MDS). The binding affinity of the hits was validated using MMGBSA, and ADMET properties of the hits were evaluated using the ADMET Lab 2.0 platform. Further, MCL-1 dependent cell lines and drug sensitivity were investigated using the DepMap CRISPRGeneEffect and CTD⌃2 dataset. Our molecular docking and MMGBSA experiment uncovered bictegravir (− 9.7 kcal/mol) and cabotegravir (− 9.3 kcal/mol) as promising inhibitors of MCL-1. Further, these integrase inhibitors exhibited appealing pharmacokinetic profiles. The 100 ns MDS further exemplifies the drugs’ structural stability in the protein active pocket. Also, our DepMap analysis identified an MCL-1 dependent cell line that exhibits moderate sensitivity to four drugs. Our findings suggest that the hit compounds could be repurposed for MCL-1-dependent cancers. However, further studies involving in vitro and in vivo experimental biological models are required to establish their novel anticancer activity.

Network analysis has provided valuable insights into the mechanisms underlying the hepatoprotective effects of manganese (Mn) in rats subjected to atrazine (ATZ) intoxication. Key hub genes, including STAT3, PPARG, GSK3B, HIF1A, ESR1, START1, MTOR, PPARA, PARP1, and MMP2, were identified as being involved in oxidative stress response, signalling pathways, nuclear receptor activity, ligand-activated transcription factor activity, and the prolactin signalling pathway. This study also employed in vivo toxicology methods to elucidate the multifaceted mechanisms of Mn-mediated hepatoprotection. Male Wistar rats (n = 30, ± 150 g) were randomly assigned into five groups and treated by gavage for 28 consecutive days: Control (corn oil), ATZ alone (10 mg/kg), Mn alone (10 mg/kg), ATZ + Mn (2.5 mg/kg each), and ATZ + Mn (10 mg/kg each). On day 29, body weights were measured, and biochemical assessments were conducted to evaluate antioxidant enzyme profiles, inflammatory biomarkers, oxidative stress markers, and liver function. Treatment with ATZ significantly reduced (p < 0.05) body weight gain compared to the control group. Markers of liver and kidney dysfunction (AST, ALT, ALP, LDH, GGT, creatinine, and urea) were significantly elevated (p < 0.05) in the ATZ-treated rats. Exposure to ATZ also decreased (p < 0.05) in endogenous antioxidant defences, including superoxide dismutase, catalase, glutathione peroxidase, total sulfhydryl, reduced glutathione, and glutathione-S-transferase. Furthermore, administration of ATZ increased (p < 0.05) oxidative stress and inflammatory biomarkers (xanthine oxidase, hydrogen peroxide, nitric oxide, myeloperoxidase, reactive oxygen and nitrogen species, and lipid peroxidation), as well as DNA fragmentation. Remarkably, Mn treatment (2.5 and 10 mg/kg) counteracted these alterations, mitigating oxidative stress, inflammation, and DNA damage induced by ATZ. Network toxicology findings corroborated these in vivo results, highlighting the ameliorative effects of Mn on ATZ-induced hepatorenal toxicity through diverse biochemical pathways. In conclusion, this study demonstrates that Mn exerts significant hepatoprotective effects against ATZ-induced toxicity, as evidenced by network pharmacology and experimental data insights. The findings suggest that Mn mitigates oxidative stress, inflammation, and hepatorenal damage through multiple molecular and biochemical mechanisms. Not applicable.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling and a promising therapeutic target for the treatment of type 2 diabetes mellitus. Ocimum gratissimum (African basil) has been traditionally used and reported to enhance insulin sensitivity and promote glucose uptake, however, the molecular basis and active constituents responsible for these biological activities remain poorly characterized. The study focused on bioprospecting O. gratissimum for PTP1B inhibitors through machine learning (ML) and molecular modeling. Predictive ML models were developed using a curated IC50 bioactivity dataset of known PTP1B inhibitors from the ChEMBL database. Among 42 algorithms assessed, the Random Forest Regressor (RFR) exhibited the best performance and identified 49 compounds (pIC(50) > 5) out of 156-screened phytochemicals. Molecular docking and 100-ns molecular dynamics (MD) simulations revealed luteolin, isovitexin, and morin as top binders, forming stable hydrogen bonds and hydrophobic interactions with key catalytic residues (CYS215 and ARG221) of PTP1B. Structural dynamics analysis further revealed the stability and conformational flexibility of the flavonoid-PTP1B complexes, while Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations supported their strong and favorable binding affinities in a dynamic environment. Overall, these findings suggest that luteolin, isovitexin, and morin may serve as potent, non-covalent PTP1B inhibitors, offering mechanistic insight into the insulin-sensitizing potential of O. gratissimum and supporting its ethnopharmacological use in diabetes management. Further experimental validation is recommended to explore and confirm their therapeutic relevance.

Motivation:Investigating novel drug-target interactions is crucial for expanding the chemical space of emerging therapeutic targets in human diseases. Herein, we explored the interactions of dipeptidyl peptidase-4 and protein tyrosine phosphatase 1B with selected terpenoids from African antidiabetic plants. Results:Using molecular docking, molecular dynamics simulations, molecular mechanics with generalized Born and surface area solvation-free energy, and density functional theory analyses, the study revealed dipeptidyl peptidase-4 as a promising target. Cucurbitacin B, 6-oxoisoiguesterin, and 20-epi-isoiguesterinol were identified as potential dipeptidyl peptidase-4 inhibitors with strong binding affinities. These triterpenoids interacted with key catalytic and hydrophobic pockets of dipeptidyl peptidase-4, demonstrating structural stability and flexibility under dynamic conditions, as indicated by dynamics simulation parameters. The free energy analysis further supported the binding affinities in dynamic environments. Quantum mechanical calculations revealed favorable highest occupied molecular orbital and lowest unoccupied molecular orbital energy profiles, indicating the suitability of the hits as proton donors and acceptors, which likely enhance their molecular interactions with the targets. Moreover, the terpenoids showed desirable drug-like properties, suggesting their potential as safe and effective dipeptidyl peptidase-4 inhibitors. These findings may pave the way for the development of novel antidiabetic agents and nutraceuticals based on these promising in silico hits. Availability and implementation:Not applicable.

Acetylcholinesterase (AChE) inhibition is a key strategy in the treatment of Alzheimer's disease and other neurodegenerative disorders. While pregnane-based compounds have been suggested as AChE inhibitors, their mechanism of action remains unclear. This study employed machine learning (ML) and molecular modeling to probe the molecular interaction of AChE with steroidal pregnanes. The ML models were trained and validated on AChE bioactivity datasets to predict pIC50 and pKi values of small-molecule compounds. Among the models tested, the Random Forest Regressor demonstrated superior performance and was used to identify pregnanes with pIC50 ≥ 5 and pKi ≥ 7 as promising inhibitors. Molecular docking revealed strong molecular interactions between AChE and several pregnanes, particularly 21-[(3-Hydroxy-2-naphthyl)oxy]pregnane-2-one. This compound interacted with critical sub-sites within the AChE binding gorge, including the catalytic active site, peripheral anionic site, oxyanion hole, and anionic sub-site, through multiple hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations over 100 ns indicated structural stability and conformational flexibility of representative AChE-pregnane complexes as indicated by the dynamic parameters and cluster patterns. The Molecular Mechanics with Generalized Born Surface Area free energy analysis confirmed strong binding affinities, while residual energy decomposition provided insights into key residue contributions. Additionally, the pregnanes demonstrated favorable blood-brain barrier permeability and other drug-like properties, suggesting their potential as neurotherapeutic agents. Given their predicted bioactivity, strong interactions with AChE, and drug-like properties, the identified pregnanes warrant further optimization and experimental evaluation for the development of safe and effective AChE inhibitors.

Prostate cancer is a major cause of cancer-related mortality in men worldwide. The anti-proliferative activity of Gongronema latifolium leaf extracts on some cancer cells has been reported. Herein, we investigated the growth inhibitory effect of the Gongronema latilolium leaf methanol extract and isolated pregnane (iloneoside) against prostate cancer cell lines using the MTT cell proliferation assay, apoptosis quantification, cell cycle analysis using flow cytometry and computational analysis molecular docking, molecular dynamics simulation (MDs), binding free energy computation and cluster analysis. In addition, UPLC-ESI-TOFMS chemical fingerprinting of previously isolated compounds was performed. The extract inhibited the growth of the cell lines with an IC50 of 49.3 µg/ml and 28.4 µg/ml for 24 h and 48 h, respectively, for PC3; and 43.7 µg/ml and 22.3 µg/ml for 24 h and 48 h, respectively, for DU145. Iloneoside demonstrated low inhibitory activities against PC3 and DU145 (IC50 > 80 μM). Apoptotic quantification and cell cycle analysis further showed that iloneoside induced apoptosis in a few cells at a dose of 200 uM. The ensemble-based molecular docking of the iloneoside to BCL-XL and BCL-2 proteins, and docking to MCL-1, BCL-A1 and BFL-1 proteins, respectively, presented binding energies of −7.22 ± 0.5, −8.12 ± 0.55, −7.1, −7.2 and −6.3 kcal/mol, while the MM/PBSA binding free energy was −25.72 ± 7.22 and −27.76 ± 11.32 kcal/mol for BCL-XL and BCL-2 proteins. Furthermore, iloneoside was stable during the 100 ns MDs analysis, while the clustering of the MDs trajectories showed that the interactions were strongly preserved. Iloneoside, in part, or in synergy with other constituents, may be responsible for the antiproliferative activities of the leaf, subject to further investigation.

Excessive fluoride exposure beyond the tolerable limit may adversely impacts brain functionality. Betaine (BET), a trimethyl glycine, possesses antioxidant, anti-inflammatory and anti-apoptotic functions, although the underlying mechanisms of the role of BET on fluoride-induced neurotoxicity remain unelucidated. To assess the mechanism involved in the neuro-restorative role of BET on behavioural, neurochemical, and histological changes, we employed a rat model of sodium fluoride (NaF) exposure. Animals were treated with NaF (9 mg/kg) body weight (bw) only or co-treated with BET (50 and 100 mg/kg bw) orally uninterrupted for 28 days. We obtained behavioural phenotypes in an open field, performed negative geotaxis, and a forelimb grip test, followed by oxido-inflammatory, apoptotic, and histological assessment. Behavioural endpoints indicated lessened locomotive and motor and heightened anxiety-like performance and upregulated oxidative, inflammatory, and apoptotic biomarkers in NaF-exposed rats. Co-treatment with BET significantly enhanced locomotive, motor, and anxiolytic performance, increased the antioxidant signalling mechanisms and demurred oxidative, inflammatory, and apoptotic biomarkers and histoarchitectural damage in the cerebrum and cerebellum cortices mediated by NaF. The in-silico analysis suggests that multiple hydrogen bonds and hydrophobic interactions of BET with critical amino acid residues, including arginine (ARG380 and ARG415) in the Keap1 Kelch domain, which may disrupt Keap1-Nrf2 complex and activate Nrf2. This may account for the observed increased in the Nrf2 levels, elevated antioxidant response and enhanced anti-inflammatory response. The BET-Keap1 complex was also observed to exhibit structural stability and conformational flexibility in solvated biomolecular systems, as indicated by the thermodynamic parameters computed from the trajectories obtained from a 100 ns full atomistic molecular dynamics simulation. Therefore, BET mediates neuroprotection against NaF-induced cerebro-cerebellar damage through rats’ antioxidant, anti-inflammatory, and anti-apoptotic activity, which molecular interactions with Keap1-Nrf2 may drive.

The use of Gongronema latifolium for the management of various forms of neurological disorders has generated a lot of interest in the need to further investigate its neurotherapeutic constituents. This work, therefore, focused on assessing the inhibitory potential of selected bioactive components derived from G. latifolium against key neurotherapeutic targets and oxidant species associated with neurodegeneration using in vitro analysis and biomolecular modelling. G. latifolium methanol extract (GLME), solvent partition, chromatographic fractions (A-F) of GLME and pregnane compounds (Iloneoside and marsectohexol) derived from fraction-B with the highest activity were investigated for in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO) inhibition in addition to their in vitro antioxidant activities. The interactions of iloneoside, marsectohexol, and reference drugs with human acetylcholinesterase, butyrylcholinesterase, and β-secretase (BACE-1) were further assessed using molecular docking, binding free energy calculations, cluster analysis, and molecular dynamics simulations. The GLME and fractions inhibited the activities of both acetylcholinesterase and butyrylcholinesterase in a dose-dependent manner. Iloneoside and marsectohexol exhibited in vitro concentration-dependent inhibitory activities against acetylcholinesterase (IC50 = 19.28, 184.9 µM, respectively) and butyrylcholinesterase (IC50 = 30.75, 43.4 µM, respectively). These compounds also possess ferric ion-reducing, hydroxyl, and superoxide radical-scavenging activities. Iloneoside had the highest docking scores of −9.8, −9.9 −9.4 Kcal for AChE, BChE, and BACE1, respectively. The stability of the interaction of the bioactive compounds with the catalytic residues of the protein targets was preserved in a 100 ns molecular dynamics simulation. Iloneoside, a rare pregnane glycoside, was identified as a neurotherapeutic constituent of G. latifolium leaf. Further studies are suggested to investigate the neurotherapeutic potential in animal models.

Triple-negative breast cancer (TNBC) is a lethal and aggressive breast cancer subtype. It is characterized by the deficient expression of the three main receptors implicated in breast cancers, making it unresponsive to hormone therapy. Hence, an existing need to develop a targeted molecular therapy for TNBC. The PI3K/AKT/mTOR signaling pathway mediates critical cellular processes, including cell proliferation, survival, and angiogenesis. It is activated in approximately 10–21

Background Neurodegenerative disorders (NDDs) are associated with increased activities of brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) as well as Aβ-amyloid (Aβ) neurotoxicity; therefore, they offer a therapeutic option for the treatment of NDDs such as Alzheimer’s disease (AD). This study was aimed at identifying multi-targeting neurotherapeutics from Gongronema latifolium leaves using in vitro analysis, GC–MS profiling and computational methods. Results The n -hexane solvent partition fraction of the methanol extract of Gongronema latifolium leaf (HF) exhibited concentration-dependent inhibitory activities against acetylcholinesterase and butyrylcholinesterase but not against MOA in vitro. The GC–MS chemical profiling identified 17 phytochemicals from the HF; these were further screened against human AChE, BChE, β-secretase enzyme (BACE1) and amyloid-β (Aβ) fibrils using molecular docking, ensemble-based docking (EBD), molecular dynamics simulation (MDs) and binding free energy (BFG) coupled with predictive adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis. The lead phytochemicals (LPs) (dihydroactinidiolide and 1H-Indole-3-ethanamine), with mean binding energies (− 6.525 ± 0.895 and 6.475 ± 0.985; − 6.833 ± 0.461 and − 6.466 ± 0.577; − 6.2 ± 0.845 and − 5.95 ± 0.353 kcal/mol) exhibited multi-target binding tendencies to the catalytic residues of hAChE, hBChE and hBACE1, in addition to hAβ fibril-disruptive tendencies (− 6.325 ± 0.545 and − 5.95 ± 0.353 kcal/mol), respectively. These results corroborated the initial molecular docking and BFG computations. The lead phytochemical–protein complexes were stable during the period of MDs. The LP presented favorable drug-likeness and ADMET properties coupled with the capacity to traverse the BBB. Conclusion Dihydroactinidiolide and 1H-Indole-3-ethanamine, in part or in synergy, are identified as neurotherapeutic constituents of Gongronema latifolium that may have been responsible for the ethnopharmacologically reported neurotherapeutic activities of the leaf, and hence they are suggested as potential drug candidates that can be useful for managing or treating neurodegenerative disease such as Alzheimer's disease, subject to further investigation.

Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against h AChE, h BChE and h BACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for h AChE, h BChE and h BACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and − 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3’ and flip (67–75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation.

Motivation Beta vulgaris (beet) is extensively reported for its antihypertensive activity. However, the mechanismunderpinning its antihypertensive activity is not well understood. In this study, we evaluated the in silico interactionsof 70 compounds derived from beta vulgaris against the active sites of angiotensin-converting enzyme (ACE) and alpha-adrenergic receptor (AR).Results Structure-based virtual screening against angiotensin-converting enzyme revealed that, Cochliophilin A (-9.0 Kcal/mol), Miraxanthin (-8.3 Kcal/mol), and quercimeritrin (-9.7 Kcal/mol) had lower docking scores than the reference lisinopril (-7.9 Kcal/mol). These compounds exhibited dual binding tendency as they also ranked top compounds upon screening against adrenergic receptor. The thermodynamic parameters computed from the resulting trajectories obtained from the 100 ns full atomistic molecular dynamics simulation revealed structural stability and conformational flexibility of the ligand-receptor complexes as indicated by the RMSD, RMSF, RoG, SASA, and H-bond calculations. The molecular mechanics with generalized Born and surface area solvation binding energy calculations revealed that the proteins exhibit considerable binding energy with the phytochemicals in a dynamic environment. Furthermore, the hit compounds possess good physicochemical properties and drug-likeness. Overall, cochliophilin and quercimeritrin are promising dual-target directed flavonoids from Beta vulgaris; and are suggested for further experimental and preclinical evaluation.Availability and implementation All data was provided in the manuscript.

Kigelia africana herbal products are often used traditionally to treat erectile dysfunction and other sexual complaints, but the underlying mechanism is not yet understood. This study focused on profiling the bioactive constituents of Kigelia africana fruit (KAF) using spectroscopic techniques and providing the computational models of their interactions with phosphodiesterase (PDE5) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) targets associated with erectile dysfunction. Integrated FT-IR, HPLC-MS, and GC-MS analysis revealed 152 (C1–C152) KAF compounds with highly diverse functional groups and chemical properties. Molecular docking showed several hit compounds as potential inhibitors of PDE5 and ROCK2. Post docking MMGBSA, QSAR, predictive physicochemical analysis and AdmetSAR analysis revealed that most of the hit compounds are potential drug leads. Among these, hydroxydoxepin (C3) and ritodrine (C131) exhibited the strongest interactions with PDE5, while epigallocatechin 3-O-p-coumarate (C9) and chlorogenic acid (C91) had the strongest interaction with ROCK2. The thermodynamic parameters and trajectory clusters computed from the trajectories obtained from the 100 ns full atomistic molecular dynamic (MD) simulation indicated the structural stability and conformational flexibility of the selected complexes. The MD simulation-based MMPBSA calculation further revealed strong binding affinity and energy contribution by active site residues of PDE5 towards binding the selected KAF compounds. Various computational analyses employed revealed that the catalytic residues Gln817, Val782 and Phe786 of PDE5 exhibited high interaction potential and flexibility towards C3 and C131. Overall, hydroxydoxepin, ritodrine and other phytochemicals in Kigelia africana may account for the therapeutic role of this plant in erectile dysfunction.

In recent years, utilization of Rhus coriaria L. (sumac) is upgrading not only in their culinary use and human nutrition, but also in the pharmaceutical industry, food industry and veterinary practices. This is driven by accumulating evidence that support the ethnobotanical use of this plant; in particular, advanced knowledge of the content of nutritional, medicinal and techno-functional bioactive ingredients. Herein, we discuss polyphenolic compounds as the main bioactive ingredients in Rhus coriaria L., which contribute mainly to the significance and utility of this spice. Most of the antioxidant potential and therapeutic roles of sumac are increasingly attributed to its constituent tannins, flavonoids, and phenolic acids. Hydroxyphenyl pyranoanthocyanins and other anthocynins are responsible for the highly desired red pigments accounting for the strong pigmentation capacity and colorant ability of sumac. Certain polyphenols and the essential oil components are responsible for the peculiar flavor and antimicrobial activity of sumac. Tannin-rich sumac extracts and isolates are known to enhance the food quality and the oxidative stability of animal products such as meat and milk. In conclusion, polyphenol-rich sumac extracts and its bioactive ingredients could be exploited towards developing novel food products which do not only address the current consumers' interests regarding organoleptic and nutritional value of food, but also meet the growing need for 'clean label' as well as value addition with respect to antioxidant capacity, disease prevention, and health promotion in humans.

The anti-apoptotic Bcl-2 family is intrinsically involved in regulating apoptosis. Over expression of these proteins is associated with cancer. Thus, inhibitors of these proteins will enhance the development of anti-apoptotic drugs. Herein, previously reported 103 Ocimum gratissimum derived phytochemicals were screened against five anti-apoptotic BCL-2 proteins (BCL-2, MCL-1, BCL-B BCL-XL and BFL-1) to identify potential inhibitors of multiple anti-apoptotic Bcl-2 proteins, using static and dynamic docking simulations, molecular dynamics (MD) simulations, clustering and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) filtering analysis. Based on the minimal binding energy and a comparative reference inhibitors binding mode analysis, five lead phytochemicals (FLP) (ursolic acid, beta-sitosterol, luteolin, basilimoside and apigenin 7,4',dimethyl ether) were identified. Ursolic acid, β-sitosterol and luteolin exhibited higher binding tendencies to the BH3 binding groove of multiple targets. Ursolic acid-Bcl-2 and luteolin-BCL-XL, complexes demonstrated structural stability in the simulated MD environment. Also, the FLP demonstrated favorable ADMET properties. Evidences from previously reported antiproliferative activities of ursolic acid, β-sitosterol and luteolin and results from this study suggest that the anti-proliferative activity of O. gratissimum may be as a result of the synergistic activities of, at least, the FLP. They are recommended for further study as natural-inhibitors against cancers defined by over expression of Bcl-2 family protein.

Vernonia amygdalina, a widely consumed West African food herb, can be a boon in the discovery of safe anti-obesity agents given the extensive reports on its anti-obesity and antidiabetic potentials. The main aim of this study was to screen 78 Vernonia-Derived Phytocompounds (VDPs) against the active site regions of Human Pancreatic Lipase (HPL), Human Pancreatic Amylase and Human Glucosidase (HG) as drug targets associated with obesity in silico. Structure-based virtual screening helped to identify Luteolin 7-O-glucuronoside and Andrographidoid D2 as hit compounds with dual targeting tendency towards the HPL and HG. Analysis of the molecular dynamic simulation trajectory files of the ligand-receptor complexes as computed from the thermodynamic parameters plots showed not only increased flexibility and greater interaction potential of the active site residues of the receptor towards the VDPs as indicated by the root mean square fluctuation but also higher stability as indicated by the root mean square deviation, radius of gyration and number of hydrogen bonds. The cluster analysis further showed that the interactions with important residues were preserved in the dynamic environment. These observations were further verified from Molecular Mechanics Generalized Born Surface Area Analysis, which also showed that residual contributions to the binding free energies were mainly from catalytic residues at the active sites of the enzymes. The hit compounds also feature desirable physicochemical properties and drug-likeness. This study provides in silico evidence for the inhibitory potential of phytochemicals from Vernonia amygdalina against two target enzymes in obesity.

ABSTRACT The anti-apoptotic Bcl-2 family is intrinsically involved in regulating apoptosis. Over expression of these proteins is associated with cancer. Thus, inhibitors of these proteins will enhance the development of anti-apoptotic drugs. Herein, previously reported 103 Ocimum gratissimum derived phytochemicals were screened against five anti-apoptotic BCL-2 proteins (BCL-2, MCL-1, BCL-B BCL-XL and BFL-1) to identify potential inhibitors of multiple anti-apoptotic Bcl-2 proteins, using static and dynamic docking simulations, molecular dynamics (MD) simulations, clustering and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) filtering analysis. Based on the minimal binding energy and a comparative reference inhibitors binding mode analysis, five lead phytochemicals (FLP) (ursolic acid, beta-sitosterol, luteolin, basilimoside and apigenin 7,4’,dimethyl ether) were identified. Ursolic acid, β-sitosterol and luteolin exhibited higher binding tendencies to the BH3 binding groove of multiple targets. Ursolic acid-Bcl-2 and luteolin-BCL-XL, complexes demonstrated structural stability in the simulated MD environment. Also, the FLP demonstrated favorable ADMET properties. Evidences from previously reported antiproliferative activities of ursolic acid, β-sitosterol and luteolin and results from this study suggest that the anti-proliferative activity of O. gratissimum may be as a result of the synergistic activities of, at least, the FLP. They are recommended for further study as natural-inhibitors against cancers defined by over expression of Bcl-2 family protein.