In silico pharmacology最新文献

Wound infection poses a significant global health threat, as it is a leading cause of morbidity and mortality among surgical patients and individuals with burn injuries, resulting in substantial healthcare burdens and devastating outcomes worldwide. Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli have frequently been implicated as major pathogens causing wound infections. This has eventually and consistently given rise to antimicrobial resistance divulging a need to mitigate infectious outbreaks. Herein, we employed a computational density functional theory (DFT) method at ωB97XD/6-311++g(d, p) level of theory to evaluate the performance of the thiophene derivative 5-(4-bromo-5-(methylthio)thiophen-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol 4, which is experimentally synthesized into five compounds (4a, 4b, 4c, 4d, and 4e). The chemical reactivity, kinetic stability, nature of interactions and functional characteristics of the thiophene derivatives were ascertained. The resistance gene PDB ID: 1K25, 2D45, 4UOT, and 7K2X were employed and docked with thiophene derivatives. Interestingly, molecular docking analysis demonstrated that ligands 4a, 4b, 4c, 4d, and 4e are more effective against proteins 1K25, 4U0T and 7K2X than amoxicillin and methicillin. Upon docking with the 2D45 protein, compounds 4c and 4e (- 5.9 kcal/mol) exhibited potential similar to that of methicillin (- 5.9 kcal/mol), while 4a and 4b showed slightly better affinities (- 6.1 kcal/mol and 6.0 kcal/mol). Using Lipinski's Rule of Five (Ghose filter, Veber rules, Muegge filter, and Egan's rule), 4d and 4e were determined to be the most promising candidates for drug development due to their compliance with all evaluated criteria, indicating favourable properties for oral bioavailability and drug likeness. This research suggested that thiophene derivatives can serve as promising antibacterial agents against wound-infected bacteria.

Antibiotic resistance microorganisms (ARMs), particularly gram-negative bacteria, pose a global health threat. The effects of fermentation on phytochemicals are numerous, and exploring this potential is the focus of drug development. The study investigated the role of fermentation in modifying V. amygdalina leaf secondary metabolites as an effective antibiotic against Escherichia. coli, Bacillus subtilis and Salmonella typhi. This work showed that fermentation increased the content of lycopene, flavonoid and carotenoid compounds but decreased chlorophyll, soluble protein and phenol. Pearson's correlation heatmap showed a strong correlation between microbial activities and secondary metabolic changes. The methanolic extract of fermented V. amygdalina leaf pulp (at day 9) showed significant antioxidant and anti-inflammatory activities. The GCMS and FTIR results showed unique compounds and structural modifications at different intervals of the fermentation period. In-vitro and in-silico analyses showed that fermentation did not alter the inhibition rate against B. subtilis; however, E. coli and S. typhi were significantly inhibited by fermented V. amygdalina pulp extracts. In-silico analyses showed that 4,6-Cholestadien-3β-ol- a compound present only on the ninth day of fermentation-was responsible for the inhibition of the gram-negative bacteria via the substitution of multiple non-ionic interactions of some key catalytic site residues with non-ionic types, thereby denying ionisation and salt-bridge properties that porins explore to resist antibiotics; and higher binding affinity to OmpC and OmpF than ampicillin. Therefore, this steroid-derived compound may open a new pipeline for developing ion-independent multi-target antibiotics against broad-spectrum multidrug-resistant gram-positive and gram-negative bacteria in food and pharmaceutical purposes.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00277-2.

Liv-52, an herbal formulation consisting of seven distinct plants and Mandur Bhasma, is recognized for its hepatoprotective, anti-inflammatory, and antioxidant properties. To investigate the pharmacological potential of each phytochemical from these plants, we conducted ADMET analysis, molecular docking, and molecular dynamic simulations to identify potent molecules capable of inhibiting the interaction between Alpha-fetoprotein (AFP) and Cysteine aspartyl protease 3 (Caspase-3/CASP3). In our study, we have used molecular docking of all the compounds against AFP and filtered them on the basis of ADME properties. Among the compounds analyzed, (-) Syringaresinol from Solanum nigrum, exhibited good binding interactions with AFP, the highest binding free energy, and maintained stability throughout the simulation along with favorable drug likeness properties based on ADME and Toxicity analysis. These findings have strongly indicated that (-) Syringaresinol is a potential inhibitor of AFP, providing a promising therapeutic avenue for hepatocellular carcinoma (HCC) treatment by inhibiting the interaction between AFP and CASP3, thereby reinstating normal CASP3 activity. Further in vitro studies are imperative to validate the therapeutic efficacy of (-) Syringaresinol as an AFP inhibitor, potentially impeding the progression of HCC.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00285-2.

Modulation of the Wnt/β-catenin signaling pathway may aid in discovering new medications for the effective management of pulmonary artery hypertension (PAH). Given the therapeutic potential of Mucuna pruriens in several diseases, the present study aimed to analyze interactions of different bioactive compounds of Mucuna pruriens plant seeds with Wnt/β-catenin pathway targeting its various components like Wnt 3a, Frizzled 1, LRP 5/6, β-catenin, Disheveled, cyclin D1 by in silico analysis. The proposed work is based on computational analysis including ADME/T properties, by a Swiss ADME server. To understand the molecular interaction pattern Schrodinger, suit a stand-alone software was used to predict the interaction of bioactive molecules of Mucuna Pruriens with target proteins that are involved in Wnt/ β catenin pathway. Further, the simulation pattern of the top docked complex was subjected to MD simulation in Desmond for 100 ns. Bioactive molecules from Mucuna Pruriens have drug-like properties and minimal toxicity. Further, the docking study revealed that among the nine compounds, three compounds (Gallic acid, L-dopa, and β-sitosterol) showed good interaction with target proteins. As gallic acid showed good interaction with all target proteins, the docked complex was subjected to MD simulation which was stable throughout the simulation time in terms of RMSD and RMSF. These findings suggest that the bioactive molecules of Mucuna pruriens compounds have potential therapeutic value in the treatment of pulmonary vascular disease. Further, in vivo and in vitro studies are necessary to determine its efficacy and validate its pharmacological activity conclusively.

Estrogen hormone dependence accounts for a major cause in the incidence of women breast cancer. ER-α is the major ER subtype in the mammary epithelium and plays a critical role in breast cancer progression. Tamoxifen (1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2- diphenylbut-1(Z)-ene) is a nonsteroidal antiestrogen prodrug which formed pharmacologically active metabolite, 4-hydroxytamoxifen, largely used for endocrine therapy in pre and postmenopausal women with ER-positive breast cancer. However, long term treatment with tamoxifen results in acquires resistance and high probability of disease recurring, hence the need for an alternative breast cancer drug. In silico approach was used to investigate the inhibitory activities of a novel dimeric flavanonol OC251FR2 (3,3'-oxybis(5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one)-3,3'-oxybis(5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one) isolated from the chloroform fraction of Garcinia kola, against alpha Estrogen receptor (ER-α); a major contributor to the growth of breast cancer. The docking was conducted using Maestro module 13.5 to obtained the ER-α PDB (5W9C) from NCBI. The OC251FR2 was docked using ligprep module with 4-hydroxytamoxifen being the reference drug. The qikpro was used to investigate the drug-likeliness while ligand docking and induced fit docking were used to investigate the interaction and binding affinity of the ligands with the active sites of the PDB. The result shows that the isolated OC251FR2 with docking score value of -6.214 interact more with amino acids in the active sites via H-bond, pi-pi interaction than the reference drug 4-Hydroxytamoxifen with a docking score value of -5.289. The drug-likeliness determined by qikpro shows that OC251FR2 violated three of the Lipinski rules of 5, and also have percent oral absorption. The quantum mechanics values show that OC251FR2 have similar properties comparable to the reference drug 4-hydroxytamoxifen. Hence, can serve as potential lead against alpha Estrogen receptor (ER-α).

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00282-5.

The study investigated the efficacy of Campomanesia xanthocarpa infusions on human melanoma cells (SK-MEL-28). The phytochemical profile revealed 18 phenolic compounds in the leaf infusion and 9 in the fruit infusion. After 24 h of treatment, the infusions demonstrated antineoplastic effects, reducing cell viability at all tested concentrations for the leaf infusion. For the fruit infusion, a significant reduction in cell viability was observed specifically at the 800 μg/mL concentration. Fluorescence microscopy and mitochondrial membrane potential results indicated that the leaf infusion was more effective in reducing cell viability and mitochondrial function in SK-MEL-28 cells, possibly due to its greater variety of phenolic compounds compared to the fruit infusion. The leaf infusion also induced higher production of intracellular reactive oxygen species compared to the fruit infusion. Protein sulfhydryl levels were reduced for the leaf infusion. Epigallocatechin gallate, Isoquercitrin, Rutin, Kaempferol-3-O-rutinoside, Chlorogenic acid, and Ellagic acid were identified as the main compounds with activity against SK-MEL-28 cells. Molecular docking analysis underscored factors such as affinity, cavity size, binding mode, and contact residues with specific compounds chosen for their favorable properties in targeting BRAF, CDK4, CDK6, MEK1, and MEK2. The variability in binding affinities may directly influence the compounds' ability to inhibit different signaling pathways related to cancer cell growth and proliferation. The results suggest that phenolic compounds from C. xanthocarpa extracts have therapeutic potential and could contribute to melanoma therapies.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00286-1.

Steroid 5α-reductase (5αR) converts testosterone into dihydrotestosterone (DHT), a potent androgen driving prostate cell proliferation via the androgen receptor (AR). Both 5αR and AR play crucial roles in androgen-mediated disorders, making them key therapeutic targets in drug development. Current treatments target these enzymes individually and often cause significant side effects, highlighting the need for safer alternatives. Through in silico screening, 13 pyrrolizidine alkaloids of Heliotropium indicum (HI) were assessed for their inhibitory potential against 5αR and AR. Using machine learning, six alkaloids showed promising pIC50 values. The accuracy of the models was assessed using key statistical parameters, including the score, correlation coefficient for training sets (R²), correlation coefficient for test sets (Q²), standard deviation (SD), and root mean square error (RMSE). For 5αR, the results were 0.763 (R²), 0.781 (Q²), 0.748 (score), 0.362 (SD), and 0.832 (RMSE), while for AR, the values were 0.817 (R²), 0.783 (Q²), 0.713 (score), 0.427 (SD), and 0.782 (RMSE), indicating reliability. Europine-N-oxide (-10.27 kcal/mol) and Heliotridine-N-oxide (-9.72 kcal/mol) displayed stronger 5αR binding than Finasteride, while Heliotrine (-10.09 kcal/mol) and Europine-N-oxide (-8.76 kcal/mol) outperformed Enzalutamide in AR binding. Key hydrogen bonds and MD simulations confirmed stable interactions. Pharmacokinetic screening revealed favorable drug-like profiles, including good solubility and absorption with minimal CYP enzyme inhibition. These findings suggest that HI alkaloids are promising multi-target inhibitors for BPH treatment, warranting further in vivo validation and optimization.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00280-7.

Staphylococcus aureus, a notorious member of the ESKAPE pathogens, poses significant public health challenges due to its virulence and multidrug-resistant nature, particularly in methicillin-resistant S. aureus (MRSA) strains. With the increasing threat of antibiotic resistance, there is an urgent need to develop novel antibiotic agents. This study therefore aims to explore the antibacterial potential of 1,2-dibenzoylhydrazine (DBH) as a scaffold against S. aureus drug target enzymes, using integrated computational approaches. The study utilized molecular docking, lead optimization, and structure-based virtual screening techniques to evaluate the binding affinities of DBH and its derivatives against various S. aureus enzymes. Prime/MM-GBSA calculations were performed to validate the binding affinities obtained, and molecular dynamics (MD) simulations were conducted to assess the stability of the DBHs-enzyme complexes. Results indicated that, out of twenty enzymes from S. aureus examined against DBH, carotenoid dehydrosqualene synthase was predicted as a suitable target enzyme for DBH, showing a binding affinity of -8.027 kcal/mol. A lead optimization operation of the compound generated 27 DBH derivatives out of which four exhibited enhanced binding affinities compared to both DBH and a standard antibiotic, ofloxacin. The QSAR model predicted that, DBH and molecule_D_1 have higher PIC₅₀ of 4.779 µM compared with the standard drug (ofloxacin = 4.678 µM). MD simulations confirmed the stability of the top-scoring derivatives within the enzyme's binding pocket, with RMSD and RMSF analyses supporting their potential as inhibitors of the enzyme. In conclusion, this study has predicted the effect of DBH derivatives on S. aureus based on their in silico inhibitory capacity against the carotenoid dehydrosqualene synthase from the organism. Future work will seek to experimentally validate these findings against the suggested enzyme.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00278-1.

Lung Cancer remains a significant health concern, necessitating the exploration of novel therapeutic avenues due to the limited efficacy and adverse effects of current treatments. In this study, we utilized a thorough in-silico and in-vitro methodology to develop prospective drugs for the treatment of lung cancer. The active components of Citrus latifolia were identified through the utilization of a variety of pharmacological instruments, such as Gene Ontology, GeneCards, DrugBank, the Chinese Traditional Drug Database, and GeneMANIA. Subsequent molecular docking studies using GOLD software revealed Hesperidin as the most promising candidate, exhibiting a remarkable binding affinity (GOLD score: 60.98 kcal/mol) towards the epidermal growth factor receptor (EGFR), a pivotal target in lung cancer therapy. Further validation through Schrodinger-Glide redocking reaffirmed the robust interaction between Hesperidin and EGFR. Pharmacokinetic profiling of top-scoring ligands indicated favorable drug-like properties, supporting their therapeutic potential. Molecular dynamics simulations employing Desmond software demonstrated the structural stability and persistence of the Hesperidin-EGFR complex over a 100-ns trajectory, corroborating its efficacy. Additionally, cytotoxicity analysis revealed a potent inhibitory effect of Hesperidin with an IC₅₀ value of 34.25 µg/ml. Collectively, our findings underscore Hesperidin from Citrus latifolia as a promising candidate for lung cancer therapy, warranting further investigation through in-vivo studies for clinical translation.

Graphical abstract:

This study used various assays to analyse the antioxidant activity and phenolic content of Ornithogalum narbonense flowers. The DPPH radical scavenging activity was found to have an IC₅₀ value of 1276.00 µg/mL, the iron chelating activity was 5.12 mg/mL, and the total flavonoid content was 33.14 mg QE/g extract ± 4.76. Gas chromatography analysis identified various bioactive compounds, with ethane, 1,1-diethoxy- being the most dominant at 52.87% of the total area. Molecular docking studies revealed that 3,5-Di-tert-butylphenol and 9-Octadecene exhibit significant binding affinity with human ferritin L chain (2FFX), suggesting their potential to influence iron chelation activity. Toxicity evaluations showed LD50 values of 800 mg/kg for 3,5-Di-tert-butylphenol and 2760 mg/kg for 9-Octadecene, categorising them into toxicity classes 4 and 5. Both compounds demonstrated minimal activity across various toxicity models. However, they displayed specific interaction profiles with targets such as Prostaglandin G/H Synthase 1 and Amine Oxidase A. In-silico cytotoxicity predictions highlighted the potential anticancer activity of 3,5-Di-tert-butylphenol against Hs 683 oligodendroglioma cells and 9-Octadecene against A2058 melanoma cells. These findings emphasise the anticancer potential of O. narbonense phytochemicals and the significance of molecular docking and toxicity profiling in drug discovery.