In silico pharmacology最新文献

Parkinson's disease, a neurodegenerative disorder, is quickly progressing and accounts for 15% of dementia cases. Parkinson's disease is the second most frequent form of neuronal degeneration after Alzheimer's, with an average age of 55 years for individuals exhibiting neuropsychiatric and physiological symptoms. Due to the effectiveness, low toxicity, and low side effects, bioactive compounds from plants have received increased attention recently as therapeutic drugs. In the current study, effective anti-neurodegenerative phytochemicals from Dodonaea viscosa were screened using in silico methods and have been proposed to be further investigated for the treatment of Parkinson's disease. The structures of twenty bioactive chemicals were screened and graph theoretical network analysis revealed alpha-synuclein as a potent therapeutic target. Based on docking scores, an effective bioactive molecule was selected, and its energy values, electrostatic potential surface and drug-like qualities were examined using molecular orbitals, pharmacokinetics and toxicity studies. Pinocembrin was found as a superior binder based on molecular docking as it demonstrated stronger binding with - 10.2 kcal/mol. An investigation using Ramachandran plot validated the protein-ligand complex secondary structure's stability. Pinocembrin, a bioactive phytochemical from Dodonaea viscosa, may be a viable lead molecule that may be developed as a candidate medicine for anti-neurodegenerative therapy against Parkinson's disease.

Mucormycosis is a concerning invasive fungal infection with difficult diagnosis, high mortality rates, and limited treatment options. Iron availability is crucial for fungal growth that causes this disease. This study aimed to computationally target iron uptake proteins in Rhizopus arrhizus, Lichtheimia corymbifera, and Mucor circinelloides to identify inhibitors, thereby halting fungal growth and intervening in mucormycosis pathogenesis. Seven important iron uptake proteins were identified, modeled, and validated using Ramachandran plots. An in-house antifungal library of ~ 15,401 compounds was screened in molecular docking studies with these proteins. The best small molecule-protein complexes were simulated at 100 ns using Maestro, Schrodinger. Toxicity predictions suggested all six molecules, identified as the best binding compounds to seven proteins, belonged to lower toxicity levels per GHS classification. A molecular mechanics GBSA study for all seven complexes indicated low standard deviations after calculating free binding energies every 10 ns of the 100 ns trajectory. Density functional theory via quantum mechanics approaches highlighted the HOMO, LUMO, and other properties of the six best-bound molecules, revealing their binding capabilities and behaviour. This study sheds light on the molecular mechanisms and protein-ligand interactions, providing a multi-dimensional view towards the use of FDBD01920, FDBD01923, and FDBD01848 as stable antifungal ligands.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00264-7.

Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372 g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66 kcal/mol, followed by binding affinity of - 7.4 kcal/mol and - 7.8 kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45 kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65 kcal/mol and 8.16 kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.

Urtica dioica (stinging nettle) has been traditionally used in Chinese medicine for the treatment of joint pain and rheumatoid arthritis. This study aims to elucidate the active compounds and mechanisms by which it acts against gout arthritis (GA). Gout-related genes were identified from the DisGeNet, GeneCards, and OMIM databases. These genes may play a role in inhibiting corresponding proteins targeted by the active compounds identified from the literature, which have an oral bioavailability of ≥ 30% and a drug-likeness score of ≥ 0.18. A human protein-protein interaction network was constructed, resulting in sixteen clusters containing plant-targeted genes, including ABCG2, SLC22A12, MAP2K7, ADCY10, RELA, and TP53. The key bioactive compounds, apigenin-7-O-glucoside and kaempferol, demonstrated significant binding to SLC22A12 and ABCG2, suggesting their potential to reduce uric acid levels and inflammation. Pathway enrichment analysis further identified key metabolic pathways involved, highlighting a dual mechanism of anti-inflammatory and urate-lowering effects. These findings underscore the potential of U. dioica in targeting multiple pathways involved in GA, combining traditional medicine with modern pharmacology. This integrated approach provides a foundation for future research and the development of multi-target therapeutic strategies for managing gout arthritis.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00254-9.

Dengue virus, an arbovirus of genus Flavivirus, is an infectious disease causing organisms in the tropical environment leading to numerous deaths every year. No therapeutic is available against the virus till date with only symptomatic relief available. Here, we have tried to design therapeutic compounds from scratch by fragment based method followed by pharmacophore based modelling to find suitable similar structure molecules and validated the same by MD simulation, followed by binding energy calculations and ADMET analysis. The receptor binding region of the dengue envelope protein was considered as the target for prevention of viral host cell entry and thus infection. This resulted in the final selection of kanamycin as a stable binding molecule against the Dengue virus envelope protein receptor binding domain. This study results in selection of a single molecule having high binding energy and prominent stable interactions as determined by post simulation analyses. This study aims to provide a direction for development of small molecule therapeutics against the dengue virus in order to control infection. This study may open a new avenue in the arena of structure based and fragment based therapeutic design to obtain novel molecules with therapeutic potential.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00262-9.

The cAMP-responsive element binding protein (CREB) binding protein (CBP), a bromodomain-containing protein, engages with multiple transcription factors and enhances the activation of many genes. CBP bromodomain acts as an epigenetic reader and plays an important role in the CBP-chromatin interaction which makes it an important drug target for treating many diseases. Though inhibiting CBP bromodomain was reported to have great potential in cancer therapeutics, approved CBP bromodomain inhibitor is yet to come. We utilized various in silico approaches like molecular docking, ADMET, molecular dynamics (MD) simulations, MM-PBSA calculations, and in silico PASS predictions to identify potential CBP bromodomain inhibitors from marine natural compounds as they have been identified as having distinctive chemical structures and greater anticancer activities. To develop a marine natural compound library for this investigation, Lipinski's rule of five was used. Sequential investigations utilizing molecular docking, ADMET studies, 100 ns MD simulations, and MM-PBSA calculations revealed that three marine compounds-ascididemin, neoamphimedine, and stelletin A-demonstrated superior binding affinity compared to the standard inhibitor, 69 A. These compounds also exhibited suitable drug-like properties, a favorable safety profile, and formed stable protein-ligand complexes. The in-silico PASS tool predicted that these compounds have significant potential for anticancer activity. Among them, ascididemin demonstrated the highest binding affinity in both molecular docking and MM-PBSA calculations, as well as a better stability profile in MD simulations. Hence, ascididemin can be a potential inhibitor of CBP bromodomain. However, in vitro and in vivo validation is required for further confirmation of these findings.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00258-5.

Targeted delivery of therapeutic anticancer chimeric molecules enhances drug efficacy. Numerous studies have focused on developing novel treatments by employing cytokines, particularly interleukins, to inhibit the growth of cancer cells. In the present study, we fused interleukin 24 with the tumor-targeting peptide P20 through a rigid linker to selectively target cancer cells. The secondary structure, tertiary structure, and physicochemical characteristics of the constructed chimeric IL-24-P20 protein were predicted by using bioinformatics tools. In-silico analysis revealed that the fusion construct has a basic nature with 175 amino acids and a molecular weight of 20 kDa. By using the Rampage and ERRAT2 servers, the validity and quality of the fusion protein were evaluated. The results indicated that 93% of the chimeric proteins contained 90.1% of the residues in the favoured region, resulting in a reliable structure. Finally, docking and simulation studies were conducted via ClusPro and Desmond Schrödinger, respectively. Our results indicate that the constructed fusion protein exhibits excellent quality, interaction capabilities, validity, and stability. These findings suggest that the fusion protein is a promising candidate for targeted cancer therapy.

The metabolic disorder Type 2 Diabetes Mellitus (T2DM) is characterized by hyperglycaemia, causing increased mortality and healthcare burden globally. Recent studies emphasize the impact of metabolites in the gut microbiome on T2DM pathogenesis. One such microbial metabolite, imidazole propionate (Imp) derived from histidine metabolism, is shown to interfere with insulin signalling and other key metabolic processes. The key enzyme urocanate reductase (UrdA) is involved in ImP production. Hence, we propose to develop a novel therapeutic vaccine against the gut microbe producing Imp based on UrdA as a target for treating T2DM using immunoinformatics approach. Antigenic, non-allergic, non-toxic, and immunogenic B cell and T cell potential epitopes were predicted using immunoinformatics servers and tools. These epitopes were adjoined using linker sequences, and to increase immunogenicity, adjuvants were added at the N-terminal end of the final vaccine construct. Further, to confirm the vaccine's safety, antigenic and non-allergic characteristics of the developed vaccine construct were assessed. The tertiary structure of the UrdA vaccine sequence was predicted using molecular modelling tools. A molecular docking study was utilized to understand the vaccine construct interaction with immune receptors, followed by molecular dynamics simulation and binding free energy calculations to assess stability of the complex. In silico cloning techniques were employed to evaluate the expression and translation effectiveness of the developed vaccine in pET vector. In conclusion, this study developed an in silico epitope-based vaccine construct as a novel adjunct therapeutic for T2DM.

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Oxadiazoles an important heterocyclic scaffold of medicinal importance in the field of drug discovery. In the study, a library of oxadiazole based compounds was selected for screening against STAT-3 as anti-cancer target. STAT3 is a potential target of interest in cancer therapy. A total of 544 screened library of compounds was subjected to molecular docking against STAT-3 (6NJS and 6NQU). The compounds with good dock score and binding interations were further subjected to in-silico ADME analysis followed by toxicity estimation. A total of 141 hits were selected against 6NJS and 50 hits against 6NQU and further screened for kinetic properties and drug likeliness. The compounds were screened on the basis of physico-chemical properties, solubility, gastrointestinal absorption, BBB permeability, synthetic accessibility, Lipinski and other violations. Best compounds obtained after ADME analysis were further subjected for toxicity analysis. Carcinogenecity, mutagenicity, Ames and other important parameters were considered for toxicity based screening. The best leads thus obtained (compound 114 and 40) were further subjected to molecular dynamics against the respective target proteins. MD simulations were run to access the stability of C-114 and C-40 along with the dynamic behaviour of both complexes for about 100 ns and shows good stability with the proteins.

Postprandial hyperglycemia (PPG) exacerbates endothelial dysfunction and impairs vascular function in diabetes as well in healthy people. Though synthetic drugs are available to regulate PPG, the severe gastrointestinal side effects of those medications have prompted the search for alternative treatments. Recently, some phytochemicals captured the attention because of their inhibitory effects on α-amylase to control diabetes. The aim of this study was to investigate and identify potential alpha-amylase inhibitors in C. indica and W. coagulans. This study also aims to understand one of the possible mechanisms of action of plants for their anti-diabetic activity. A total of 36 phytochemical ligands were subjected for protein-ligand docking analysis. Among the phytochemicals, Taraxerol and Epoxywithanolide-I demonstrated significant binding free energy of - 10.2 kcal/mol and - 11.9 kcal/mol respectively, which was higher than the reference acarbose with - 8.6 kcal/mol. These molecules were subjected for molecular dynamics simulation (MDS) analysis with alpha-amylase protein for a duration of 150 ns. Among the three complexes, Taraxerol and Epoxywithanolide-I complexes demonstrates strong potential as inhibitors of the target protein. MDS results were analyzed via root mean square deviation (RMSD), fluctuation of residues, potential energy, radii of gyration and solvent access surface area analysis. Taraxerol demonstrated a significantly low potential energy of - 1,924,605.25 kJ/mol, and Epoxywithanolide-I demonstrated - 1,964,113.3 kJ/mol of potential energy. RMSD plot shows that Epoxywithanolide-I has much higher stability than the other MDS complexes. Drugability and toxicity studies show that the test ligands are demonstrating strong potential as drug like molecules. The results of the study conclude that, Taraxerol of C. indica and Epoxywithanolide-I of W. coagulans are strong inhibitors of alpha-amylase enzyme and that, this is one of the possible mechanisms of action of the plants for their reported anti-diabetic activities. Further in-vitro analysis is in demand to prove the observed results.