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Data implicating the mutation in penicillin-binding protein (PBP) 3 and occasionally PBP5 in the resistance of Escherichia coli to beta−lactams is intriguing. Thus, the identification of an improved class of inhibitors of PBP3 and PBP5 is imperative, and in this study, phenolics due to their promising antibacterial activities were screened using structure−based pharmacophore and molecular docking approaches against PBP3, and the ability of the lead phenolics to modulate PBP3 and PBP5 was studied using molecular dynamics simulation. The results demonstrated various inhibitory capacities of the lead phenolics, with lysidicichin (−41.66 kcal/mol) and silicristin (−31.11 kcal/mol) being the most potent against PBP3, while epicatechin 3-O-(3-O-methylgallate) (−38.97 kcal/mol) and epigallocatechin-4-benzyl thioether (−37.01 kcal/mol) had higher affinities towards PBP5. Overall, epicatechin gallate had the best broad-spectrum of activity, as the compound was able to bind favourably to both targets. Additionally, the thermodynamic information confirmed the stability of the lead phenolics with both targets. Conclusively, while these observations are suggestive of the modulatory role of the lead phenolics on the growth of E. coli, further in vitro and in vivo validation of the activity elicited by the phenolics in this study is imperative, and efforts are underway in this direction. [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS), one of the deadliest global diseases, is caused by the Human Immunodeficiency Virus (HIV). To date, there are no known conventional drugs that can cure HIV/AIDS, and this has prompted continuous scientific efforts in the search for novel and potent anti-HIV therapies. In this study, molecular dynamics simulation (MDS) and computational techniques were employed to investigate the inhibitory potential of bioactive compounds from selected South African indigenous plants against HIV-1 subtype C protease (HIVpro). Of the eight compounds (CMG, MA, UA, CA, BA, UAA, OAA and OA) evaluated, only six (CMG (−9.9 kcal/mol), MA (−9.3 kcal/mol), CA (−9.0 kcal/mol), BA (−8.3 kcal/mol), UAA (−8.5 kcal/mol), and OA (−8.6 kcal/mol)) showed favourable activities against HIVpro and binding landscapes like the reference FDA-approved drugs, Lopinavir (LPV) and Darunavir (DRV), with CMG and MA having the highest binding affinities. Using the structural analysis (root-mean-square deviation (RMSD), fluctuation (RMSF), and radius of gyration (RoG) of the bound complexes with HIVpro after 350 ns, structural evidence was observed, indicating that the six compounds are potential lead candidates for inhibiting HIVpro. This finding was further corroborated by the structural analysis of the enzyme–ligand complexe systems, where structural mechanisms of stability, flexibility, and compactness of the study metabolites were established following binding with HIVpro. Furthermore, the ligand interaction plots revealed that the metabolites interacted hydrophobically with the active site amino residues, with identification of other key residues implicated in HIVpro inhibition for drug design. Overall, this is the first computational report on the anti-HIV-1 activities of CMG and MA, with efforts on their in vitro and in vivo evaluations underway. Judging by the binding affinity, the degree of stability, and compactness of the lead metabolites (CMG, MA, CA, BA, OA, and UAA), they could be concomitantly explored with conventional HIVpro inhibitors in enhancing their therapeutic activities against the HIV-1 serotype. [ABSTRACT FROM AUTHOR]

The medicinal herb Aspalathus linearis (rooibos) is globally recognized in type-2 diabetes mellitus (T2DM) treatment due to its known and distinctive compounds. This work utilized network pharmacology (NP) coupled with molecular dynamics simulation in gaining new insight into the anti-diabetic molecular mechanism of action of rooibos teas. It looked at the interactions between rooibos constituents with various relevant protein receptors and signaling routes associated with T2DM progression. The initial analysis revealed 197 intersecting gene targets and 13 bioactive rooibos constituents linked to T2DM. The interactions between proteins and compounds to the target matrix were generated with the Cystoscope platform and STRING database. These analyses revealed intersecting nodes active in T2DM and hypoxia-inducible factor 1 (HIF-1) as an integral receptors target. In addition, KEGG analysis identified 11 other pathways besides the hub HIF-1 signaling route which may also be targeted in T2DM progression. In final molecular docking and dynamics simulation analysis, a significant binding affinity was confirmed for key compound-protein matrices. As such, the identified rooibos moieties could serve as putative drug candidates for T2DM control and therapy. This study shows rooibos constituents' interaction with T2DM-linked signaling pathways and target receptors and proposes vitexin, esculin and isovitexin as well as apigenin and kaempferol as respective pharmacologically active rooibos compounds for the modulation of EGFR and IGF1R in the HIF-1 signaling pathway to maintain normal homeostasis and function of the pancreas and pancreatic β-cells in diabetics. [ABSTRACT FROM AUTHOR]

Recently, dipeptidyl peptidase-IV (DPP-IV) has become an effective target in the management of type-2 diabetes mellitus (T2D). The study aimed to determine the efficacy of shikimate pathway-derived phenolic acids as potential DPP-IV modulators in the management of T2D. The study explored in silico (molecular docking and dynamics simulations) and in vitro (DPP-IV inhibitory and kinetics assays) approaches. Molecular docking findings revealed chlorogenic acid (CA) among the examined 22 phenolic acids with the highest negative binding energy (−9.0 kcal/mol) showing a greater affinity for DPP-IV relative to the standard, Diprotin A (−6.6 kcal/mol). The result was corroborated by MD simulation where it had a higher affinity (−27.58 kcal/mol) forming a more stable complex with DPP-IV than Diprotin A (−12.68 kcal/mol). These findings were consistent with in vitro investigation where it uncompetitively inhibited DPP-IV having a lower IC50 (0.3 mg/mL) compared to Diprotin A (0.5 mg/mL). While CA showed promising results as a DPP-IV inhibitor, the findings from the study highlighted the significance of medicinal plants particularly shikimate-derived phenolic compounds as potential alternatives to synthetic drugs in the effective management of T2DM. Further studies, such as derivatisation for enhanced activity and in vivo evaluation are suggested to realize its full potential in T2D therapy. [ABSTRACT FROM AUTHOR]

The acquisition of penicillin-binding protein (PBP) 2a in resistant strains of Staphylococcus aureus allows for the continuous production of cell walls even after the inactivation of intrinsic PBPs. Thus, the discovery of novel therapeutics with enhanced modulatory activity on PBP2a is crucial, and plant secondary metabolites, such as phenolics, have found relevance in this regard. In this study, using computational techniques, phenolics were screened against the active site of PBP2a, and the ability of the lead phenolics to modulate PBP2a's active and allosteric sites was studied. The top-five phenolics (leads) identified through structure–activity-based screening, pharmacokinetics and synthetic feasibility evaluations were subjected to molecular dynamics simulations. Except for propan-2-one at the active site, the leads had a higher binding free energy at both the active and allosteric sites of PBP2a than amoxicillin. The leads, while promoting the thermodynamic stability of PBP2a, showed a more promising affinity at the allosteric site than the active site, with silicristin (−25.61 kcal/mol) and epicatechin gallate (−47.65 kcal/mol) having the best affinity at the active and allosteric sites, respectively. Interestingly, the modulation of Tyr446, the active site gatekeeper residue in PBP2a, was noted to correlate with the affinity of the leads at the allosteric site. Overall, these observations point to the leads' ability to inhibit PBP2a, either directly or through allosteric modulation with conventional drugs. Further confirmatory in vitro studies on the leads are underway. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signaling pathway, has gained attention as a validated druggable target in the management of type 2 diabetes mellitus (T2DM). The lack of clinically approved PTP1B inhibitors has continued to prompt research in plant-derived therapeutics possibly due to their relatively lesser toxicity profiles. Flavonoid C-glycosides are one of the plant-derived metabolites gaining increased relevance as antidiabetic agents, but their possible mechanism of action remains largely unknown. This study investigates the antidiabetic potential of flavonoid C-glycosides against PTP1B in silico and in vitro. Of the seven flavonoid C-glycosides docked against the enzyme, three compounds (apigenin, vitexin, and orientin) had the best affinity for the enzyme with a binding score of –7.3 kcal/mol each, relative to –7.4 kcal/mol for the reference standard, ursolic acid. A further probe (in terms of stability, flexibility, and compactness) of the complexes over a molecular dynamics time study of 100 ns for the three compounds suggested orientin as the most outstanding inhibitor of PTP1B owing to its overall -34.47 kcal/mol binding energy score compared to ursolic acid (-19.24 kcal/mol). This observation was in accordance with the in vitro evaluation result, where orientin had a half maximal inhibitory concentration (IC50) of 0.18 mg/ml relative to 0.13 mg/ml for the reference standard. The kinetics of inhibition of PTP1B by orientin was mixed-type with V max and K m values of 0.004 μM/s and 0.515 μM. Put together, the results suggest orientin as a potential PTP1B inhibitor and could therefore be further explored in the management T2DM as a promising therapeutic agent. [ABSTRACT FROM AUTHOR]

Adverse effects associated with synthetic drugs in diabetes therapy has prompted the search for novel natural lead compounds with little or no side effects. Effects of phenolic compounds from Carpobrotus edulis on carbohydrate-metabolizing enzymes through in vitro and in silico methods were assessed. Based on the half-maximal inhibitory concentrations (IC50), the phenolic extract of the plant had significant (p < 0.05) in vitro inhibitory effect on the specific activity of alpha-amylase (0.51 mg/mL), alpha-glucosidase (0.062 mg/mL) and aldose reductase (0.75 mg/mL), compared with the reference standards (0.55, 0.72 and 7.05 mg/mL, respectively). Molecular interactions established between the 11 phenolic compounds identifiable from the HPLC chromatogram of the extract and active site residues of the enzymes revealed higher binding affinity and more structural compactness with procyanidin (−69.834 ± 6.574 kcal/mol) and 1,3-dicaffeoxyl quinic acid (−42.630 ± 4.076 kcal/mol) as potential inhibitors of alpha-amylase and alpha-glucosidase, respectively, while isorhamnetin-3-O-rutinoside (−45.398 ± 4.568 kcal/mol) and luteolin-7-O-beta-d-glucoside (−45.102 ± 4.024 kcal/mol) for aldose reductase relative to respective reference standards. Put together, the findings are suggestive of the compounds as potential constituents of C. edulis phenolic extract responsible for the significant hypoglycemic effect in vitro; hence, they could be exploited in the development of novel therapeutic agents for type-2 diabetes and its retinopathy complication. [ABSTRACT FROM AUTHOR]

• Raphia hookeri (RH) is an underutilized palm crop native to Africa. • Its ethnomedicinal, phytochemistry and biotechnological applications are appraised. • RH's metabolites could support its inherent industrial and therapeutic significance. • "-omics" could provide supportive data on its safety and health benefits. • The study provided baseline information that will inspire further investigations on RH. Raphia hookeri G. Mann & H. Wendl (Arecaceae), commonly known as 'Raffia Palm' is an underutilized plant native to Africa. Like other palms, it is a good source of medicine with diverse ethnomedicinal and industrial applications. Despite these discernible therapeutic and economic benefits of R. hookeri , the plant remains underutilized, albeit some achievement has been made in this area. Hence, this review highlights the existing scope and knowledge gaps regarding its folkloric uses and phytochemistry with a view to lending credence to its pharmacological properties, particularly in the treatment of diabetes. Information are also provided on its biotechnological applications. Despite the pharmacological significance and ethnomedicinal uses of R. hookeri , a major challenge that persists is the lack of comprehensive data on its phytochemical characterization as well as inadequate information on its pharmacokinetics and pharmacodynamics. In view of this, the concepts of molecular dynamics and "-omics" (genomics, proteomics, metabolomics, and transcriptomics etc.) as currently being embraced as modern strategies enhancing translational studies, could find relevance and may provide more comprehensive data supporting the safety profile and therapeutic efficacy of R. hookeri against markers implicated in the pathogenesis and physiological perturbations associated with diseases. These strategies are proposed for adoption in future studies seeking to provide evidence-based data on the therapeutic scope and overall economic benefits of R. hookeri. [ABSTRACT FROM AUTHOR]

• Little variance exists between six cultivars of sunflower seeds in terms of chemical profile and abundance. • PPAR signaling pathway is mostly induce by the metabolites of sunflower seeds for its antidiabetic effect. • MMP1 and PPARA genes of the PPAR pathways is mostly modulated by the metabolites of sunflower seeds for its antidiabetic effect. • Metabolites of sunflower seeds had better affinity for MMPI gene than PPARA gene in the antidiabetic modulation of PPAR pathway. • CGA, CFG, and GPA are the active metabolites in sunflower seeds responsible for its antidiabetic effects. Helianthus annuus cypsela (sunflower) is a staple oilseed crop with significant therapeutic applications against diverse diseases including type 2 diabetes mellitus (T2DM). Despite its reported antidiabetic potential, the implicated molecular mechanism of action is yet to be unravelled to date. This study evaluated the molecular mechanism of the antidiabetic activity of sunflower cypsela using network pharmacology (NP), density functional theory, and molecular dynamics (MD) simulation approaches. The six cultivars of sunflower cypsela used were profiled for their secondary metabolites using LC-MS and GC–MS techniques. Subsequently, the genes associated with the identified metabolites were screened against T2DM-associated genes using NP. Based on the KEGG enrichment analysis of the identified common genes, signaling pathways were subsequently identified. The results obtained revealed 87 intersecting genes between the metabolites of sunflower cypsela and T2DM, while the KEGG analysis identified 35 signaling pathways with the PPAR route and its associated genes as the most implicated in T2DM progression with respect to sunflower cypsela. Both MMP1 and PPARA in the PPAR pathways interacted most with the identified metabolites, with CGA (−43.74 kcal/mol), GPA (−41.62 kcal/mol), and CFG (−45.36 kcal/mol) having higher binding free energy than both ROS and MET (reference standards) against MMP1 after 100,000 ps MD simulation. In contrast, ROS (−46.98 kcal/mol) had better affinity against PPARA compared to the top hits of sunflower cypsela. However, against both gene targets, the top hits had significant thermodynamic stability, flexibility, and compactness, which are attributable to their bond interactions and molecular orbital properties. These findings are suggestive of the essential role of the top-hits in the antidiabetic potential of sunflower cypsela through activation of the PPAR signalling pathway and most especially MMP1. In this regard, the modulation of MMP1 and PPARA genes by the identified metabolites of sunflower cypsela may enhance insulin sensitivity and glucose homoeostasis in the management of T2DM. [ABSTRACT FROM AUTHOR]

[Display omitted] • Helianthus annuus extracts, and metabolites possess LasR modulatory activity. • Distinct metabolite signatures, new H. annuus metabolites detected first time. • Pannar 7102 CLP cultivar had best quorum sensing modulatory activity against LasR. • 1,4-bis(phenylglyoxaloyl)benzene, obolactone, key leads of 5 from in-silico studies. • Top 5 metabolites; thermodynamically stable, compact, with good drug-like features. The Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔG bind) calculations revealed obolactone (−48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (−45.06 kcal/mol), cyclocanaliculatin (−43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (−39.18 kcal/mol) and lonchocarpin (−33.78 kcal/mol) as first-time putative leads relative to azithromycin (−32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections. [ABSTRACT FROM AUTHOR]