Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation.

BACKGROUND: Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors. METHODS: To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment. RESULTS: Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A. CONCLUSION: According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.

Insights from in silico exploration of major curcumin analogs targeting human dipeptidyl peptidase IV.

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, -6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to -7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme.Communicated by Ramaswamy H. Sarma.

Diabetic wound healing of aloe vera major phytoconstituents through TGF-ß1 suppression via in-silico docking, molecular dynamic simulation and pharmacokinetic studies.

To restore the integrity of the skin and subcutaneous tissue, the wound healing process involves a complex series of well-orchestrated biochemical and cellular events. Due to the existence of various active components, accessibility and few side effects, some plant extracts and their phytoconstituents are recognised as viable options for wound healing agents. To find possible inhibitors of diabetic wound healing, four main constituents of aloe vera were identified from the literature. TGF-ß1 and the compounds were studied using molecular docking to see how they interacted with the active site of target protein (PDB ID: 6B8Y). The pharmacokinetics investigation of the aloe emodin with the highest dock score complied with all the Lipinski's rule of five and pharmacokinetics criteria. Conformational change in the docked complex of Aloe emodin was investigated with the Amber simulation software, via a molecular dynamic (MD) simulation. The MD simulations of aloe emodin bound to TGF-ß1 showed the significant structural rotations and twists occurring from 0 to 200 ns. The estimate of the aloe emodin-TGF-ß1 complex's binding free energy has also been done using MM-PBSA/GBSA techniques. Additionally, aloe emodin has a wide range of enzymatic activities since their probability active (Pa) values is >0.700. 'Aloe emodin', an active extract of aloe vera, has been identified as the key chemical in the current investigation that can inhibit diabetic wound healing. Both in-vitro and in-vivo experiments will be used in a wet lab to confirm the current computational findings.Communicated by Ramaswamy H. Sarma.

Exploring the potential of biologically active phenolic acids from marine natural products as anticancer agents targeting the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) dimerizes upon ligand bindings to the extracellular domain that initiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphorylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. The main objective of this research is to discover more promising anti-cancer lead compound against EGRF from the phenolic acids of marine natural products using in-silico approaches. Phenolic compounds reported from marine sources are reviewed from previous literatures. Furthermore, molecular docking was carried out using the online tool CB-Dock. The molecules with good docking and binding energies scores were subjected to ADME, toxicity and drug-likeness analysis. Subsequently, molecules from the docking experiments were also evaluated using the acute toxicity and MD simulation studies. Fourteen phenolic compounds from the reported literatures were reviewed based on the findings, isolation, characterized and applications. Molecular docking studies proved that the phenolic acids have good binding fitting by forming hydrogen bonds with amino acid residues at the binding site of EGFR. Chlorogenic acid, Chicoric acid and Rosmarinic acid showed the best binding energies score and forming hydrogen bonds with amino acid residues compare to the reference drug Erlotinib. Among these compounds, Rosmarinic acid showed the good pharmacokinetics profiles as well as acute toxicity profile. The MD simulation study further revealed that the lead complex is stable and could be future drug to treat the cancer disease. Furthermore, in a wet lab environment, both in-vitro and in-vivo testing will be employed to validate the existing computational results.Communicated by Ramaswamy H. Sarma.

Virtual screening of pyrazole derivatives of usnic acid as new class of anti-hyperglycemic agents against PPARγ agonists.

The finest sources of therapeutic agents are natural products, and usnic acid is a secondary metabolite derived from lichen that has a wide range of biological actions, including anti-viral, anti-cancer, anti-bacterial, and anti-diabetic (hyperglycemia). Based on the hyperglycemia activity of UA, this work seeks to identify new anti-hyperglycemia medicines by virtual screening of pyrazole derivatives of UA. Seven hit compounds (Compounds 1, 5, 6, 7, 17, 18 and 33), which finally go through docking-based screening to produce the lead molecule, were identified by the physicochemical attributes, drug-likeliness, and ADMET prediction. The docking score for the chosen compounds containing PPARγ agonists ranged from -7.6 to -9.2 kcal/mol, whereas the docking goal for compounds 5, 6, and 7 was -9.2 kcal/mol. Based on the binding energy and bound amino acid residues as well as compared to the reference compound, compound-6 considered as lead compound. Furthermore, the MD simulation of 3CS8-Compound-6 and 3CS8-Rosiglitazone complexes were performed to verify the stability of these complexes and the binding posture acquired in docking experiments. The compound-6 had strong pharmacological characteristics, bound to the PPARγ agonist active site, and was expected to reduce the activity of the receptor, according to the virtual screening results. It must be justified to conduct both in-vitro and in-vivo experiments to examine the efficacy of this compound. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00176-y.

Identification of Pyrazole Derivatives of Usnic Acid as Novel Inhibitor of SARS-CoV-2 Main Protease Through Virtual Screening Approaches.

The infection produced by the SARS-CoV-2 virus remains a significant health crisis worldwide. The lack of specific medications for COVID-19 necessitates a concerted effort to find the much-desired therapies for this condition. The main protease (Mpro) of SARS-CoV-2 is a promising target, vital for virus replication and transcription. In this study, fifty pyrazole derivatives were tested for their pharmacokinetics and drugability, resulting in eight hit compounds. Subsequent molecular docking simulations on SARS-CoV-2 main protease afforded two lead compounds with strong affinity at the active site. Additionally, the molecular dynamics (MD) simulations of lead compounds (17 and 39), along with binding free energy calculations, were accomplished to validate the stability of the docked complexes and the binding poses achieved in docking experiments. Based on these findings, compound 17 and 39, with their favorable projected pharmacokinetics and pharmacological characteristics, are the proposed potential antiviral candidates which require further investigation to be used as anti-SARS-CoV-2 medication.

Virtual screening of bioactive anti-SARS-CoV natural products and identification of 3ß,12-diacetoxyabieta-6,8,11,13-tetraene as a potential inhibitor of SARS-CoV-2 virus and its infection related pathways by MD simulation and network pharmacology.

Since the first prevalence of COVID-19 in 2019, it still remains the most devastating pandemic throughout the world. The current research aimed to find potential natural products to inhibit the novel coronavirus and associated infection by MD simulation and network pharmacology approach. Molecular docking was performed for 39 natural products having potent anti-SARS-CoV activity. Five natural products showed high binding interaction with the viral main protease for the SARS-CoV-2 virus, where 3ß,12-diacetoxyabieta-6,8,11,13 tetraene showed stable binding in MD simulation until 100 ns. Both 3ß,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A targeted 11 common genes that are related to COVID-19 and interact with each other. Gene ontology development analysis further showed that all these 11 genes are attached to various biological processes. The KEGG pathway analysis also showed that the proteins that are targeted by 3ß,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A are associated with multiple pathways related to COVID-19 infection. Furthermore, the ADMET and MDS studies reveals 3ß,12-diacetoxyabieta-6,8,11,13 as the best-suited compound for oral drug delivery.Communicated by Ramaswamy H. Sarma.

Usnic acid as potential inhibitors of BCL2 and P13K protein through network pharmacology-based analysis, molecular docking and molecular dynamic simulation.

Usnic acid (UA) lately piqued the interest of researchers for its extraordinary biological characteristics, including anticancer activity. Here, the mechanism was clarified through network pharmacology,molecular docking and molecular dynamic simulation. Sixteen proteins were selected through network pharmacology study as they are probable to interact with UA. Out of these proteins, 13 were filtered from PPI network analysis based on their significance of interactions (p < 0.05). KEGG pathway analysis has also aided us in determining the three most significant protein targets for UA, which are BCL2, PI3KCA and PI3KCG. Therefore molecular docking and molecular dynamic (MD) simulations throughout 100 ns were performed for usnic acid onto the three proteins mentioned. However, UA's docking score in all proteins is lower than their co-crystalised ligand, especially for BCL2 (-36.5158 kcal/mol) and PI3KCA (-44.5995 kcal/mol) proteins. The only exception is PI3KCG which has comparable results with the co-crystallised ligand with (-41.9351 kcal/mol). Furthermore, MD simulation has also revealed that usnic acid does not stay fit in the protein throughout the simulation trajectory for PI3KCA protein evident from RMSF and RMSD plots. Nevertheless, it still poses good ability in inhibiting BCL2 and PI3KCG protein in MD simulation. In the end, usnic acid has exhibited good potential in the inhibition of PI3KCG proteins, rather than the other proteins mentioned. Thus further study on structural modification of usnic acid could enhance the ability of usnic acid in the inhibition of PI3KCG as anti-colorectal and anti-small cell lung cancer drug candidate.Communicated by Ramaswamy H. Sarma.

Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long-Evans Rats.

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

Qualitative dataset on UPLC-QTOF/MS tentative identification of phytochemicals from bioactive extract of Ipomoea mauritiana Jacq.

The current data report describes the predictive identification of phytochemical constituents in the bioactive extract of Ipomoea mauritiana (IM) whole plant. For several formulations this plant was commonly used as 'Vidari' for Ayurvedic medicine. Traditionally, IM tubers are used to alleviate spinal cord pain, improve breast milk, as a tonic, increase sperm count and treating jaundice. The methanol extract can potentially scavenge free radicals and possess antibacterial activity that could be correlated with its chemical composition. So it is crucial to identify the major compounds of IM. An ultra-performance liquid chromatography coupled electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF/MS) method was adopted to detect the flavonoids, saponins, alkaloids, terpenoids in IM methanol extract. Data presented here is related to a published work Antioxidant and antibacterial activity of Ipomoea mauritiana Jacq.: A traditionally used medicinal plant in Bangladesh (Alam et al., 2020). Secondary metabolites were analyzed by the comparison of the mass fragmentation arrangements with Waters UNIFI library that enables for positive identification of the compounds based on the spectral match.

Probing the effects of fish oil on the delivery and inflammation-inducing potential of imiquimod.

Imiquimod is a chemotherapeutic agent for many skin-associated diseases, but it has also been associated with inflammatory side effects. The aim of this study was to prevent the inflammatory effect of commercial imiquimod (Aldara(®)) by controlled release of imiquimod through a hydrogel/oleogel colloidal mixture (CA bigel) containing fish oil as an anti-inflammatory agent. Imiquimod permeability from Aldara® cream and bigel through mice skin was evaluated, and the drug content residing in the skin via the tape stripping technique was quantified. The fish oil fatty acid content in skin along with its lipophilic environment was also determined. An inflammation study was conducted using animal models, and Aldara(®) cream was found to potentially cause psoriasis-like inflammation, which could be owing to prolonged application and excessive drug permeation. Controlled release of imiquimod along with fish oil through CA bigel may have caused reduced imiquimod inflammation. NMR studies and computerized molecular modeling were also conducted to observe whether the fish oil and imiquimod formed a complex that was responsible for improving imiquimod transport and reducing its side effects. NMR spectra showed dose-dependent chemical shifts and molecular modeling revealed π-σ interaction between EPA and imiquimod, which could help reduce imiquimod inflammation.

Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents.

A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 µM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 µM and 9.6 ± 0.5 µM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.

Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.

The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 µM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.