In silico pharmacology最新文献

Alzheimer's disease (AD) is the most occurring neurodegenerative disorder that destroys learning, memory, and thinking skills. Although the pathophysiology of the disease is least understood, the post-mortem brain of AD patients as well as animal models revealed the part of down regulated Wnt signalling in progression of the disease. The deficit in the Wnt signalling leads to the accumulation of amyloid beta peptides, phosphorylation of tau proteins, and synaptic dysfunctions, which are regarded as the major pathological features of AD. As the available drugs for AD are only able to mitigate the symptoms and are also associated with several side effects, the therapeutic potential of the bioactive compounds is being explored for their efficacies in managing the major pathologies. Consequently, a few bioactive compounds fundamentally isolated from Garcinia species are established as promising neuroprotective agents in AD, however; their potential to regulate the Wnt signalling pathway is yet to be discovered. Considering the neuroprotective properties, in the present study efficiency of six small bioactive compounds viz., amentoflavone, isovitexin, orientin, apigenin, kaempferol, and garcinol have been investigated in modulating the receptor proteins (LRP6, DKK1, WIF1 and GSK3β) of the Wnt signalling pathway by molecular docking technique. While all the bioactive compounds could efficiently interact with the target proteins, amentoflavone, orientin, and isovitexin interact with all the target proteins viz., LRP6, DKK1, WIF1, and GSK3β with higher free energy of binding, more number of interactions, and similar mode of binding in comparison to their known or reported modulators. Thus, the present study set forth the investigated small bioactive molecules as potential drug candidates in AD therapeutics.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that affects people aged 60 years and above. Yet, the discovery of potent therapeutic agents against this disease has no utmost progress and a number of drug candidates could not make it out of the clinical trials at varied stages. At the same time, the currently available anti-cholinesterase (AChE) and monoamine oxidase-B (MAO-B) for the treatment of AD can only improve the clinical symptoms while the recently approved immunotherapy agent "remains questionable. Thus, the need for novel therapeutic agents with the potential to treat the aetiology of the disease. Herein, this study sought to examine the potential of a number of bioactive compounds derived from Vitis vinifera as a promising agent against AChE and MAO-B. Using a computational approach via molecular docking 23 bioactive agents were screened against AChE and MAO-B, and the compounds with a binding score below that of the standard ligand were further subjected to drug-likeness and pharmacokinetic screening. Eight and thirteen of the studied agents optimally saturated the active pocket of the AChE and MAO-B respectively, forming principal interactions with a number of amino acids at the active pocket of the targets and among these compounds only rutin failed the drug-likeness test by violating four parameters while all showed moderate pharmacokinetics features. A number of Vitis vinifera-derived bioactive compounds show excellent inhibitory potential against AChE and MAO-B, and moderate pharmacokinetic features when compared to the reference ligand (tacrine). These compounds are therefore proposed as novel AChE and MAO-B inhibitors for the treatment of AD and wet-lab analysis is necessary to affirm their potency.

The continuous search for more effective options against well-known pathogens such as Candida albicans remains the rationale for the search for novel lead compounds from various sources. This study aims to investigate the chemical structure, chemical properties, of 5-(2-((5-(((1S,3R) -3-(5-acetamido-1,3,4-thiadiazolidin-2-yl) cyclopentyl) methyl)-1,3,4-thiadiazolidin-2-yl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-pyrazol-3-ide designated ATCTP using DFT method ωB97XD/-311 +  + g(2d, 2p) and the biological potential of compound ATCTP against Candida albicans using molecular docking and ADMET studies. Geometry optimization was carried out in DMSO, ethanol. gas and water revealing minute discrepancies in bond length and wider differences in bond angles. Frontier molecular orbital investigations reveal HOMO-LUMO energy gap magnitude in decreasing order of ATCTP_Gas > ATCTP_Water > ATCTP_ethanol > ATCTP_DMSO inferring that water influences chemical stability of the compound the most compared to ethanol and DMSO. Density of state investigations have revealed electron density contributions at corresponding energy peaks. In silico pharmacokinetic predicts ATCTP not to be cytotoxic, hepatotoxic, immunotoxic or mutagenic but probable mutagen. Molecular docking investigation of ATCTP against aspartic proteinase of Candida albicans (ID: 2QZX) in comparison with standard drug Fluconazole. Compound ATCTP had higher binding affinity (- 8.1 kcal/mol) compared to that of the standard drug fluconazole (- 5.6 kcal/mol) which records 4 conventional hydrogen interactions compared to 2 formed in the interaction of ATCTP + 2QZX. ATCTP also reports binding affinity of - 7.2 kcal/mol which reportedly surpassed that of 2QZX interaction with fluconazole (- 5.7 kcal/mol). ATCTP binds with lanosterol14-α-demethylase (5v5z) with binding affinity of - 9.7 kcal/mol binding to active site amino acid residues of the protein compared to fluconazole + 5v5z (- 8.0 kcal/mol). ATCTP is therefore recommended to be a lead compound for the possible design of a new and more effective anti-candida therapeutic compound.

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Chemotherapy is one of the most well-established and effective cancer treatments available. However, non-tumor-associated damage restrict the treatment's effectiveness and safety. Our growing understanding of cancer epigenetics has resulted in new therapeutic options and the potential of better patient outcomes in recent decades. In cancer, epigenetic changes are widespread, particularly increased expression and activity of histone deacetylases (HDACs). Epi-drugs are chemical agents that modify the structure of DNA and chromatin facilitating disruption of transcriptional and post-transcriptional changes. First generation epi-drugs include HDAC inhibitors (HDACi) (approved to treat hematological malignancies) harbor various adverse effects demanding the discovery and development of potential natural HDACi that might benefit cancer treatment especially in hematological malignancies. Curcumin (diferuloylmethane), a polyphenolic, component of Curcuma longa, is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to be a pan HDACi. Yet the potential of other curcuminoids in Curcuma longa as pan HDACi remains unexplored. (i) To virtually screen curcumin and curcuminoids (Desmethoxycurcumin [DMC] & Bisdemethoxycurcumin [BDMC]) against human Histone deacetylase (HDAC) class I, II and IV enzymes in comparison to their pan HDAC inhibition activity with FDA approved human HDACis available in market and also (ii) to predict the drug likeness property and ADME/ toxicity of curcumin, curcuminoids and approved HDACis via computational approach. Homology modelling followed by docking was performed for human HDAC class I, II and IV enzymes with curcumin, Desmethoxycurcumin, Bisdemethoxycurcumin and with 5 reference HDACi compounds Vorinostat (SAHA), Trichostatin A (TSA), Chidamide, Romidepsin, and Panobinostat to understand the protein -ligand interactions and binding efficiencies. Further, the study ligands with low binding energy were predicted for pharmacokinetic properties and Lipinski's rule of 5. Our study revealed that BDMC followed by DMC and curcumin had high inhibitory effect by interacting at the active site of Zn⁺ HDACs similar to that of the standard HDACi (curcumin, DMC, BDMC, Belinostat, Chidamide, Romidepsin, Panobinostat, Trichostatin A and Vorinostat). Likewise, all of the chosen ligand molecules, with the exception of Romidepsin (refractive index > 130 m³mol^-1), adhered to Lipinski's rule of five and none of the natural compounds (curcumin, DMC, BDMC) did report any toxicity and mutagenic property also, the lethal doses (LD50) of all the natural compounds were higher when compared to chemical drugs. BDMC could be a potential pan HDACi than curcumin and DMC owing to high binding affinity among human Zn⁺ HDACs. The results of our present study can be useful for the design and development of novel compounds having better HDAC inhibitory

The collagen type I alpha 1 (COL1A1, OMIM #120,150) gene, encoding the alpha-1 chain of type I collagen (UniProt #P02452), plays a key role in life-homeostasis due to its remarkable involvement in collagen synthesis. It is a promising candidate gene implicated in the pathogenesis of cervical insufficiency (CI). This study aimed to identify genetic variations within the COL1A1 gene that contribute to the development of CI. Polymerase chain reaction (PCR) and amplicon sequencing were implemented for single nucleotide polymorphisms (SNPs) detection (+ 1245G/T, SP1 rs1800012), which revealed wild-type sequence for targeted SNPs in enrolled proband indicated negative results regarding COL1A1 gene involvement for current form of CI. It allows further investigation of other closely connected genes probed in this study. Computational approaches viz. Protein-protein interaction (PPI), gene ontology (GO), and pathway participation were used to identify the crucial hub genes and signaling pathways for COL1A1 and CI. Using the Yet Another Scientific Artificial Reality Application (YASARA) software, molecular docking, and molecular dynamic (MD) simulation with the oxytocin (CID 439,302), estradiol (CID 129,728,744), progesterone (CID 5994) and hydroxyprogesterone (CID 150,788) were done. Interactive bioinformatics analysis demonstrated that the COL1A1 and more than 10 collagen sister genes had a strong connection with CI. In sum, the findings of this study provide insights into a modus operandi that can be utilized to illuminate the path toward studying sister genes and smooth diagnosis of CI. These findings have implications for understanding the foundational process of the condition and potentially developing screening, diagnostic, and therapeutic interventions.

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Diabetes mellitus is a chronic metabolic disorder that affects glucose, lipid, and protein metabolism. Targeting these metabolic derangements can optimize the therapeutic strategies for this disease. Utilizing in vitro and in silico models, this study investigated the ability of aqueous and ethanol extracts of Irvingia gabonensis to inhibit α-amylase, α-glucosidase, pancreatic lipase, and protein glycation. High-performance liquid chromatography (HPLC) was used to identify the compounds found in the stem bark of I. gabonensis. In silico analysis determined the binding mode and mechanism of interactions between the enzymes and phytochemicals. With an IC₅₀ value of 11.47 µg/ml, the aqueous extract demonstrated higher inhibitory efficacy against α-amylase compared to the ethanol extract (IC₅₀ 19.88 µg/ml). However, the ethanol extract had stronger inhibitory activities against α-glucosidase, pancreatic lipase, and protein glycation compared to the aqueous extract (IC₅₀ values of 3.05, 32.85, 0.0014 versus 25.72, 332.42, 0.018 µg/ml respectively). Quercetin ranked highest in binding energy with α-amylase (-6.6 kcal/mol), α-glucosidase (-6.6 kcal/mol), and pancreatic lipase (-5.6 kcal/mol). This was followed by rhamnetin (6.5, 6.5, and 6.1 kcal/mol respectively). Hydrogen bonding, hydrophobic interactions, and pi-pi stacking are forces responsible for the binding of quercetin and rhamnetin to these enzymes. Molecular dynamics simulation showed that the lead phytochemicals formed stable and energetically stabilized complexes with the target proteins. This study showed that the extracts of I. gabonensis stem bark had significant in vitro anti-diabetic, anti-pancreatic lipase, and anti-protein glycation activities. The strong binding affinities of some of the identified compounds could be responsible for the inhibitory potential of the extracts. I. gabonensis stem bark could be further explored as a natural remedy for the treatment of diabetes mellitus and its complications.

Squalene (SQ) has been documented in the past for its ability to reduce inflammation, but its mechanism needs more information. In this study, we investigated squalene as an anti-inflammatory drug candidate and the framework involved in treating inflammation (INF) using the network pharmacology concept. The molecular targets of SQ and INF that are available in databases and the overlaps between these targets were demonstrated using InteractiVenn. The protein-protein networks were generated that in turn revealed several key targets and were further processed with Cytoscape. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) studies were performed. We also performed molecular docking tests that validated the binding affinity of molecular targets and drugs. A total of 100 SQ targets and 11,417 INF-related targets yielded 93 overlapping targets. Seven core targets, CRHR1, EGFR, ERBB2, HIF1A, SLC6A3, MAP2K1, and F2R were found to be relevant with respective to SQ's anti-inflammatory activity. The underlying mechanism of SQ with regard to INF was interpreted by analyzing various enrichment analyses along with the KEGG pathway. In conclusion, SQ played a vital role in the management of INF by regulating CRHR1, EGFR, ERBB2, HIF1A, SLC6A3, MAP2K1, and F2R. The research outcomes are crucial as they offer significant insights into the use of SQ for combating inflammation.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00217-0.