In silico pharmacology最新文献

This study investigated the blood‒brain barrier (BBB) permeability of the central nervous system (CNS)-active compounds donepezil (DON), methionine (MET), and memantine (MEM) by employing a comprehensive in silico approach. These compounds are of particular interest for Alzheimer's disease (AD) therapy. Rigid-flexible molecular docking simulations indicated favorable binding affinities of all the compounds with BBB-ChT, with DON exhibiting the highest binding affinity (ΔG_bind = -10.26 kcal/mol), predominantly mediated by significant hydrophobic interactions. In silico kinetic profiling suggested the stability of the DON/BBB-ChT complex, with ligand release prompted by conformational changes. 3D molecular alignment corroborated a minor conformational shift for DON in its minimal binding energy pose. Predictions indicated that active transport mechanisms notably enhance the brain distribution of donepezil compared to that of MET and MEM. Additionally, DON and MEM exhibited low mutagenic probabilities, while MET was identified as highly mutagenic. Overall, these findings highlight the potential of donepezil for superior BBB penetration, primarily through active transport mechanisms, underscoring the need for further validation through in vitro and in vivo studies for effective AD treatment.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00245-w.

Although many natural product-derived compounds possess anti-leishmanial activities in vitro and in vivo, their molecular targets in the Leishmania parasite remain elusive. This is a major challenge in optimizing these compounds into leads. The Leishmania pteridine reductase (PTR1) is peculiar for folate and pterin metabolism and has been validated as a drug target. In this study, 17 compounds with anti-leishmanial activities were screened against Leishmania major PTR1 (LmPTR1) using molecular docking and molecular dynamics (MD) simulations. All ligands were bound in the active site pocket of LmPTR1 with binding affinities ranging from -11.2 to -5.2 kcal/mol. Agnuside, betulin, betulinic acid, gerberinol, ismailin, oleanolic acid, pristimerin, and ursolic acid demonstrated binding affinities similar to a known inhibitor, methyl 1-(4-{[2,4-diaminopteridin-6-yl) methyl] amino} benzoyl) piperidine-4-carboxylate (DVP). MD simulations revealed that betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid formed stable complexes with LmPTR1. The binding free energies of the complexes were very good (-87 to -148 kJ/mol), and much higher than the complex of the standard DVP inhibitor and LmPTR1 (-27 kJ/mol). Betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid likely exert their antileishmanial action by inhibiting PTR1 and could thus be used as a basis for the development of potential antileishmanial chemotherapeutic agents.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00247-8.

The Nipah virus (NiV), a zoonotic virus in the Henipavirus genus of the Paramyxoviridae family, emerged in Malaysia in 1998 and later spread globally. Diseased patients may have a 40- 70% chance of fatality depending on the severity and early medication. The recent outbreak of NiV was reported in Kerala (India) by a new strain of MCL-19-H-1134 isolate. Currently, no vaccines are available, highlighting the critical need for a conclusive remedy. Our study aims to develop a subunit vaccine against the NiV by analyzing its proteome. NiV genome and proteome sequences were obtained from the NCBI database. A phylogenetic tree was constructed based on genome alignment. T-cell, helper T-cell, and B-cell epitopes were predicted from the protein sequences using NetCTL-1.2, NetMHCIIPan-4.1, and IEDB servers, respectively. High-affinity epitopes for human receptors were selected to construct a multi-epitope vaccine (MEV). These epitopes' antigenicity, toxicity, and allergenicity were evaluated using VaxiJen, AllergenFP-v.1.0, and AllergenFP algorithms. Molecular interactions with specific receptors were analyzed using PyRx and ClusPro. Amino acid interactions were visualized and analyzed using PyMOL and LigPlot. Immuno-simulation was conducted using C-ImmSim to assess the immune response elicited by the MEV. Finally, the vaccine cDNA was inserted into the pET28a(+) expression vector using SnapGene tool for in silico cloning in an E. coli host. The potential for an imminent outbreak cannot be overlooked. A subunit vaccine is more cost-effective and time-efficient. With additional in vitro and in vivo validation, this vaccine could become a superior preventive measure against NiV disease.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00246-9.

Epstein-Barr Virus (EBV), structurally similar to other herpes viruses, possess significant global health challenges as it causes infectious mononucleosis and is also associated with various cancers. Due to this widespread impact, an effective messenger RNA (mRNA) vaccine is paramount to help curb its spread, further underscoring the need for its development. This study, following an immunoinformatic approach, aimed to design a comprehensive mRNA vaccine against the EBV by selecting antigenic proteins, predicting Linear B-cell epitopes, cytotoxic T-cell lymphocyte (CTL) and helper T-cell lymphocyte (HTL) epitopes, and assessing vaccine characteristics. Seventy-nine EBV isolates from diverse geographical regions were examined. Additionally, the vaccine construct's physicochemical properties, transmembrane domains, solubility, and secondary structures were analysed. Molecular docking was conducted with Toll-Like Receptor 5 (TLR-5). Population coverage was assessed for selected major histocompatibility complex (MHC) alleles, and immune response was simulated. The result of this study highlighted a vaccine construct with high antigenicity, non-toxicity, and non-allergenicity and possessed favourable physicochemical properties. The vaccine's 3D structure is native-like and strongly binds with TLR-5, indicating a solid affinity with TLR-5. The selected MHC alleles provided broad universal population coverage of 89.1%, and the immune simulations suggested a robust and wide-ranging immunogenic response, activating critical immune cells, antibodies, and cytokines. These findings provide a solid foundation for further development and testing of the EBV candidate vaccine, offering potential solutions for combating EBV infections.

Plants are a treasure trove of bioactive compounds. Kedrostis foetidissima (Jacq.) Cogn. has many important phytoconstituents like cucurbitacins, rutin, and quercitin compounds. Among these compounds, Quercetin-3-O- Rhamnoside (1) has antioxidant, anti-inflammatory, anticancer properties. Rutin (2) has anti-inflammatory, antioxidant, anti-diabetic, anti-microbial, antiviral properties, 7, 10-Hexa decadienoic acid methyl ester (3) has anti-inflammatory, antioxidant, hypocholesterolemia and anticancer activities. Docosanoic acid (4) has antioxidant, α-Glucosidase inhibitory activity. 3,7,11,15-Tetra methyl hexa decan-1-ol (5) has antiviral properties. Cucurbitacin-B (6) has antipyretic, analgesic, anti-inflammatory, antimicrobial, and antitumor activities. Performance of experimental studies on phytochemicals become more difficult as the availability of compounds in small quantities, hence the computational methods becomes important for drug discovery. Based on their biological activity, compounds 1-6 were tested for in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and drug-likeness properties using the Swiss ADME online web server and the pkCSM server. All the studied compounds obey Lipinski's rule of five except compounds 1 and 2 with two and three violations each. The entire selected compounds have a good bioavailability score in the recommended range of 0 to 1. Compound 4 has high (0.85) and compounds 1 and 2 have low (0.17) oral bioavailability scores. All the selected compounds from Kedrostis foetidissima have strong pharmacological activities. Supporting this, the selected plant methanol extracts of leaf, stem callus, and tuber have shown well in vitro antibacterial activity against Bacillus subtilis, Escherichia coli, and Proteus vulgaris. Therefore, these compounds may be developed into drug molecules with additional clinical research.

Abnormal deposition or aggregation of protein alpha-synuclein and tau in the brain leads to neurodegenerative disorders. Excessive hyperphosphorylation of tau protein and aggregations destroys the microtubule structure resulting in neurofibrillary tangles in neurons and affecting cytoskeleton structure, mitochondrial axonal transport, and loss of synapses in neuronal cells. Tau tubulin kinase 1 (TTBK1), a specific neuronal kinase is a potential therapeutic target for neurodegenerative disorders as it is involved in hyperphosphorylation and aggregation of tau protein. TTBK inhibitors are now the subject of intense study, but limited numbers are found. Hence, this study involves structure-based virtual screening of TTBK1 inhibitor analogs to obtain efficient compounds targeting the TTBK1 using docking, molecular dynamics simulation and protein-ligand interaction profile. The initial analogs set containing 3884 compounds was subjected to Lipinski rule and the non-violated compounds were selected. Docking analysis was done on 2772 compounds through Autodock vina and Autodock 4.2. Data Warrior and SwissADME was utilized to filter the toxic compounds. The stability and protein-ligand interaction of the docked complex was analyzed through Gromacs and VMD. Molecular simulation results such as RMSD, Rg, and hydrogen bond interaction along with pharmacokinetic properties showed CID70794974 as the potential hit targeting TTBKl prompting the need for further experimental investigation to evaluate their potential therapeutic efficacy in Alzheimer's disease.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00242-z.

Triple-negative breast cancer (TNBC) poses a significant global health challenge due to its highly aggressive nature and invasive characteristics. Dysregulation of the Hippo pathway, a key regulator of various biological processes, is observed in TNBC, and its inhibition holds promise for impeding cancer growth. This in-silico analysis investigates the role of Transcriptional Enhanced Associate Domain 4 (TEAD4) in TNBC and its interaction with Yes Associated Protein (YAP) in cancer progression. Our results demonstrate that TEAD4 upregulation is linked to poor prognosis in TNBC, emphasizing its critical role in the disease. Moreover, we identify CID44521006, an analog of Flufenamic acid, as a potential therapeutic compound capable of disrupting the TEAD4-YAP interaction by binding to the YAP-binding domain of TEAD4. These findings underscore the significance of TEAD4 in TNBC and propose CID44521006 as a promising candidate for therapeutic intervention. The study contributes valuable insights to advance treatment options for TNBC, offering a potential avenue for the development of targeted therapies against this aggressive form of breast cancer.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00239-8.

Microbial infection management and treatment are crucial as a result of the prevalent antimicrobial resistance issue. Progressive studies are being carried out on how to develop drugs that can mitigate the resistance trends of these microorganisms. Secondary metabolites of plants can also be employed and accessed for this role, as the current study examines the antibacterial activities of phytochemicals from three (3) plants (Cucubita moschata, Cucubita maxima, and Irvingia gabonesis) through computational approaches. Molecular docking studies were carried out to show the binding affinities of the phytochemicals against two target receptors (DNA gyrase and Penicillin Binding Protein 3). In addition, drug likeness analysis, bioactivity and oral-bioavailability properties, absorption, distribution, metabolism, and excretion (ADME) profiling, as well as prediction of activity spectra for substances (PASS) using online tools like SwissADME, PASS online, AdmetSAR2, and Discovery Studio, were also performed. The results obtained identified isochlorogenic acid and apigenin-7-O-glucoside for DNA gyrase (1KZN) and apigenin-7-O-glucoside for Penicillin Binding Protein 3 (4BJP), which were further subjected to molecular dynamics simulation (MDS) and therefore recommended as the lead compounds.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is the leading cause of dementia in elderly individuals. Currently, there is no permanent treatment option available for this disorder, and the existing drug regimens are associated with limited effectiveness and side effects. To evaluate the neuroprotective effect of rosemary compounds, an extensive study was started with gas chromatography-mass spectrometry (GC-MS) analysis. GC-MS was performed to study the composition of rosemary essential oil and a total of 120 volatile compounds were identified. The 36 compounds from GC-MS data of rosemary essential oil having > 1% concentration in the oil were selected along with 3 already reported well-known non-volatile compounds of rosemary. se39 bioactive natural compounds of rosemary were docked against ACE, BACE1, GSK3, and TACE proteins, which are involved in AD progression. The top 3 compounds against each target protein were selected based on their binding energies and a total of 6 compounds were found as best candidates to target the AD; α Amyrin, Rosmanol, Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta), Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl), Methyl abietate, and Rosmarinic acid were the best compounds. The binding energy of α-Amyrin, Rosmanol, and Androsta-1,4-dien-3-one,16,17-dihydroxy-(16.beta.,17.beta) to ACE target is -10 kcal/mol, -9.3 kcal/mol, and - 9.3 kcal/mol, respectively. The best binding affinity was shown by complexes formed between GSK3-α-Amyrin (-9.1 kcal/mol), BACE1- α-Amyrin (-9.9 kcal/mol), and TACE- Benzenesulfonamide,4-methyl-N-(5-nitro-2-pyridinyl) (-9.1 kcal/mol). The comparative analysis between known inhibitors/ drugs of target proteins and the rosemary compound that shows the highest binding affinity against each protein also revealed the higher potential of rosemary natural compounds in terms of binding energy. The drug-likeliness properties like Lipinski's rule of five and the ADME/T analysis of top-selected compounds were screened through PkCSM and Deep-PK tools. The findings from this study suggested that rosemary compounds have the potential as a therapeutic lead for treating AD. This kind of experimental confirmation can lead to novel drug candidates against the pharmacological targets of AD.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00238-9.

The present study investigated the neuroprotective properties of whole plants of Grewia bilamellata Gagnep. extract (GBEE) against cerebral ischemia by harnessing both In vivo studies in a rat model and In silico studies focusing on nitric oxide synthase (NOS) inhibition. High-resolution liquid chromatography‒mass spectrometry (HR LC‒MS) analysis identified 32 phytochemicals in the GBEE, 15 of which adhered to Lipinski's rule of five. These compounds exhibited diverse physicochemical properties and high binding affinity to NOS, with cleomiscosin D showing the greatest potential. In vivo, GBEE had significant neuroprotective effects on bilateral common carotid artery occlusion/reperfusion (BCCAO/R) in rats, especially at doses of 200 mg/kg and 400 mg/kg body weight. GBEE treatment improved brain function, as evidenced by EEG normalization, substantial reductions in cerebral infarction size, mitigated neuronal loss, and the restoration of regular histological arrangement in the CA1 hippocampal area of the brain. Furthermore, GBEE enhanced antioxidant defenses by augmenting the activity of catalase (CAT) and superoxide dismutase (SOD), reducing malondialdehyde (MDA) levels, and restoring reduced glutathione (GSH) levels. These effects were accompanied by a decrease in nitric oxide (NO) levels, indicative of attenuated oxidative and nitrosative stress. Collectively, our findings suggest that GBEE is a promising natural therapeutic agent that may prevent or alleviate ischemic brain injury through a multifaceted mechanism involving NOS inhibition and attenuation of the oxidative stress response. This study highlights the therapeutic potential of GBEE and warrants further research into its mechanism of action and possible clinical applications.