Phytochemical profiling,in vitro biological activities,and in-silico molecular docking studies of Typha domingensis

A comparative study between methanolic extract and n-hexane fraction of Typha domingensis (Typhaceae) was conducted for the evaluation of phytochemical potential, in vitro biological activities, and in-silico molecular docking studies. The phytochemical composition was estimated by total phenolic and total flavonoid contents, and by GC–MS analysis. Several biological activities were performed such as antioxidant assays (ABTS, FRAP, DPPH, & CUPRAC), enzyme inhibition activity (Tyrosinase, Acetylcholinesterase & Butyrylcholinesterase), thrombolytic activity, and antimicrobial activity (antibacterial & antiviral) to evaluate the medicinal importance of Typha domingensis. The results of the comparative study showed that methanolic extract has more total phenolic and total flavonoid contents (95.72 ± 5.76 mg GAE/g, 131.66 ± 7.92 mg QE/g, respectively) as compared to n-hexane fraction which confirms its maximum antioxidant potential (ABTS 114.31 ± 8.17, FRAP 116.84 ± 3.01, DPPH 283.54 ± 7.3 & CUPRAC 284.16 ± 6.5 mg TE/g). In the case of in vitro enzyme inhibition study and thrombolytic activity, better results were observed for methanolic extract. Almost similar antimicrobial patterns were observed for both methanolic extract and n-hexane fraction of Typha domingensis. The major bioactive phytochemicals identified by GC–MS were further analyzed for in-silico molecular docking studies to determine the binding affinity between ligands and the enzymes. The docking study indicated that most of the bioactive compounds showed a better binding affinity with enzymes as compared to the standard compounds (kojic acid & galantamine). The results of this study recommended that Typha domingensis has promising pharmaceutical importance and it should be further analyzed for the isolation of bioactive phytochemicals which may be useful for the treatment of several diseases.     

Evaluation of in vitro,in silico antidiabetic and antioxidant potential of bioactivity based isolated “Pakistanine” from Berberis baluchistanica

Bioassay based fractionation of methanolic extract of Berberis baluchistanica (Berberidaceae), used traditionally for internal injuries, led to the isolation of known compounds (1–4). The structure of these compounds was elucidated by different spectroscopic analysis and available literature data. Antidiabetic and antioxidant potentials of B. baluchistanica fractions and isolated compounds were evaluated using in vitro alpha- amylase and DPPH assays. The isolated compounds were identified as obamegine (1), pakistanine (2), 8-oxyberberine (3) and baluchistine (4). Obamegine was reported from many other species of this genus but it is first time isolated from B. baluchistanica in present study. Moreover, in vitro pakistanine (2) was found as bioactive lead molecule for hypoglycemic (IC₅₀:40.26 µg/ml) and antioxidant (IC₅₀:14.15 µg/ml) activities compared to acarbose (IC₅₀:33.68 µg/ml) and ascorbic acid (IC₅₀:0.41 µg/ml). To the best of our knowledge, no previous data were available for these biological activities. Additionally, in silico antidiabetic and antioxidant activity of pakistanine against two proteins, α-amylase (-9.7 kcal/mol) and tyrosinase (-8.7 kcal/mol) are reported here for the first time. The molecular docking binding interactions authenticate and support the above-mentioned activities and are helpful in predicting the mechanism of action of pakistanine (2).     

Effect of selected dopants on conductivity and moisture stability of Li3PS4 sulfide solid electrolyte: a first-principles study

The first principle computational screening was performed to investigate the effect of selected dopants for Li₃PS₄ sulfide solid electrolyte on its ionic conductivity and stability toward moisture. The results suggest that substitution P⁵⁺ using isovalent cations whose electronegativity (EN) value is closer to the value of S has more significant effects on the ionic conductivity, whereby W⁵⁺ and Sb⁵⁺ can improve most. Similarly, aliovalent cation substitutions with compensating changes in the lithium-ion concentration, particularly those with a lower oxidation state and higher EN, such as Cu²⁺, effectively enhance the lithium-ion conductivity in this structure. For cation dopants, it is found that ionic conductivity improvement of Li₃PS₄ is the synergetic effect of EN and oxidation number of the dopant as well as the material's lattice parameter change. Oxides of the considered cation dopants can also improve the ionic conductivity of the material but have much lower lithium-ion conductivity than the cases of cation dopants. However, the metal oxide dopants, particularly those derived from soft Lewis' acid cations, show a marginal improvement in moisture stability of the Li₃PS₄ electrolyte. The effect of halides and metal halide dopants on the lithium-ion conductivity and moisture stability of Li₃PS₄ electrolyte are also studied. It is found that metal halides are more effective than any other dopants in improving the ionic conductivity of Li₃PS₄.     

Crowned Macrocycles Containing Two Pyrrolo[1,2-a] Indoles Created By Intramolecular Fusion

Heterocyclic fused-ring systems are of utmost importance because of their presence in many natural products with biological activity. Pyrroloindoles are tricyclic heterocycles that are present in various bioactive and medicinally valuable compounds. Herein, we report the synthesis of phenylene-bridged bis-pyrrolo[1,2-a]indole crowned macrocycles 1 – 3 in which the pyrrolo[1,2-a]indole moieties were formed via intramolecular fusion. The macrocycles were thoroughly characterized by 1D and 2D NMR, HRMS and X-ray crystallographic studies. The X-ray structure revealed that the two pyrrolo[1,2-a]indole moieties were parallel to each other, and one pyrrolo[1,2-a]indole unit was deviated by an angle of 9.54° while the other pyrrolo[1,2-a]indole unit was deviated by an angle of 12.0° from the mean plane defined by 28 core atoms. The macrocycles 1 – 3 absorb in the visible region and readily undergo oxidations because of their electron rich nature. The macrocycles 1 – 3 upon treatment with trifluoroacetic acid (TFA) generates the corresponding cation radicals 1 – 3 ^.+ which were stable in the open air for a week. The cation radicals 1 – 3 ^.+ absorb strongly in the NIR region and the experimental observations on crowned macrocycles 1 – 3 were corroborated by DFT and TD-DFT studies.     

Atomistic De-novo Inhibitor Generation-Guided Drug Repurposing for SARS-CoV-2 Spike Protein with Free-Energy Validation by Well-Tempered Metadynamics

Computational drug design is increasingly becoming important with new and unforeseen diseases like COVID-19. In this study, we present a new computational de novo drug design and repurposing method and applied it to find plausible drug candidates for the receptor binding domain (RBD) of SARS-CoV-2 (COVID-19). Our study comprises three steps: atom-by-atom generation of new molecules around a receptor, structural similarity mapping to existing approved and investigational drugs, and validation of their binding strengths to the viral spike proteins based on rigorous all-atom, explicit-water well-tempered metadynamics free energy calculations. By choosing the receptor binding domain of the viral spike protein, we showed that some of our new molecules and some of the repurposable drugs have stronger binding to RBD than hACE2. To validate our approach, we also calculated the free energy of hACE2 and RBD, and found it to be in an excellent agreement with experiments. These pool of drugs will allow strategic repurposing against COVID-19 for a particular prevailing conditions.     

Elucidating the Binding Mode between Heparin and Inflammatory Cytokines by Molecular Modeling

Heparan sulfate (HS) interacts with a broad spectrum of inflammatory cytokines, thereby modulating their biological activities. It is believed that there is a structural-functional correlation between each protein and sugar sequences in the HS polysaccharides, however, the information in this regard is limited. In this study, we compared the binding of four inflammatory cytokines (CCL8, IL-1beta, IL-2 and IL-6) to immobilized heparin by an SPR analysis. To define the molecular base of the binding, we used a heparin pentasaccharide as representative structure to dock into the 3D-molecular structure of the cytokines. The results show a discrepancy in K_D values obtained by SPR analysis and theoretical calculation, pointing to the importance to apply more than one method when describing affinity between proteins and HS. By cluster analysis of the complex formed between the pentasaccharide and cytokines, we have identified several groups in heparin forming strong hydrogen bonds with all four cytokines, which is a significant finding. This molecular and conformational information should be valuable for rational design of HS/heparin-mimetics to interfere cytokine-HS interactions.     

Identification of 3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors against Trypanothione Reductase from Leishmania Infantum Using Molecular Docking and ADMET Prediction

Polyphenolic and Terpenoids are potent natural antiparasitic compounds. This study aimed to identify new drug against Leishmania parasites, leishmaniasis’s causal agent. A new in silico analysis was accomplished using molecular docking, with the Autodock vina program, to find the binding affinity of two important phytochemical compounds, Masticadienonic acid and the 3-Methoxycarpachromene, towards the trypanothione reductase as target drugs, responsible for the defense mechanism against oxidative stress and virulence of these parasites. There were exciting and new positive results: the molecular docking results show as elective binding profile for ligands inside the active site of this crucial enzyme. The ADMET study suggests that the 3-Methoxycarpachromene has the highest probability of human intestinal absorption. Through this work, 3-Methoxycarpachromene and Masticadienonic acid are shown to be potentially significant in drug discovery, especially in treating leishmaniasis. Hence, drug development should be completed with promising results.     

Identification,Characterization and Antihypertensive Effect In Vivo of a Novel ACE-Inhibitory Heptapeptide from Defatted Areca Nut Kernel Globulin Hydrolysates

The areca (Areca catechu L.) nut kernel (ANK) is a good potential protein source for its high protein content of 9.89–14.62 g/100 g and a high yield of around 300,000 tons per year in China. However, utilization of the areca nut kernel is limited. To expand the usage of ANK in pharmaceutical or foods industries, areca nut kernel globulin was extracted and angiotensin-I converting enzyme (ACE) inhibition peptides were prepared and identified using gel chromatography, reversed phase HPLC separation, UPLC-ESI-MS/MS analysis and in silico screening. Finally, a novel ACE-inhibitory heptapeptide (Ala–Pro–Lys–Ile–Glu–Glu–Val) was identified and chemically synthesized. The combination pattern between APKIEEV and ACE, and the inhibition kinetics, antihypertensive effect and endothlein-1 inhibition activity of APKIEEV were studied. The results of the molecular docking demonstrated that APKIEEV could bind to four active sites (not the key active sites) of ACE via short hydrogen bonds and demonstrated high ACE-inhibitory activity (IC₅₀: 550.41 μmol/L). Moreover, APKIEEV exhibited a significantly lowering effect on both the systolic blood pressure and diastolic blood pressure of spontaneously hypertensive rats, and had considerable suppression ability on intracellular endothelin-1. These results highlight the potential usage of APKIEEV as ingredients of antihypertensive drugs or functional foods.     

Prediction of African Swine Fever Virus Inhibitors by Molecular Docking-Driven Machine Learning Models

African swine fever virus (ASFV) causes a highly contagious and severe hemorrhagic viral disease with high mortality in domestic pigs of all ages. Although the virus is harmless to humans, the ongoing ASFV epidemic could have severe economic consequences for global food security. Recent studies have found a few antiviral agents that can inhibit ASFV infections. However, currently, there are no vaccines or antiviral drugs. Hence, there is an urgent need to identify new drugs to treat ASFV. Based on the structural information data on the targets of ASFV, we used molecular docking and machine learning models to identify novel antiviral agents. We confirmed that compounds with high affinity present in the region of interest belonged to subsets in the chemical space using principal component analysis and k-means clustering in molecular docking studies of FDA-approved drugs. These methods predicted pentagastrin as a potential antiviral drug against ASFVs. Finally, it was also observed that the compound had an inhibitory effect on AsfvPolX activity. Results from the present study suggest that molecular docking and machine learning models can play an important role in identifying potential antiviral drugs against ASFVs.     

Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na⁺/K⁺-ATPase. The docking profiles for digoxin and several derivatives and Na⁺/K⁺-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na⁺/K⁺-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na⁺/K⁺-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.