Herbal medications have an extensive history of use in treating various diseases, attributed to their perceived efficacy and safety. Traditional medicine practitioners and contemporary healthcare providers have shown particular interest in herbal syrups, especially for respiratory illnesses associated with the SARS-CoV-2 virus. However, the current understanding of the pharmacokinetic and toxicological properties of phytochemicals in these herbal mixtures is limited. This study presents a comprehensive computational analysis utilizing novel approach methodologies (NAMs) to investigate the pharmacokinetic and toxicological profiles of phytochemicals in herbal syrup, leveraging in-silico techniques and prediction tools such as PubChem, SwissADME, and Molsoft's database. Although molecular dynamics, docking, and broader system-wide analyses were not considered, future studies hold potential for further investigation in these areas. By combining drug-likeness with molecular simulation, researchers identify diverse phytochemicals suitable for complex medication development examining their pharmacokinetic-toxicological profiles in phytopharmaceutical syrup. The study focuses on herbal solutions for respiratory infections, with the goal of adding to the pool of all-natural treatments for such ailments. This research has the potential to revolutionize environmental and alternative medicine by leveraging in-silico models and innovative analytical techniques to identify novel phytochemicals with enhanced therapeutic benefits and explore network-based and systems biology approaches for a deeper understanding of their interactions with biological systems. Overall, our study offers valuable insights into the computational analysis of the pharmacokinetic and toxicological profiles of herbal concoction. This paves the way for advancements in environmental and alternative medicine. However, we acknowledge the need for future studies to address the aforementioned topics that were not adequately covered in this research.

• Klíčová slova
• ADME/Tox Profiling, Drug-Likeness, In-silico Analysis, Pharmacokinetics, Phytochemicals, Toxicology,
• Publikační typ
• časopisecké články MeSH

Multidrug-resistant (MDR) Staphylococcus aureus infections significantly threaten global health. With rising resistance to current antibiotics and limited solutions, the urgent discovery of new, effective, and affordable antibacterials with low toxicity is imperative to combat diverse MDR S. aureus strains. Hence, in this study, we introduce an in silico phytochemical-based approach for discovering novel antibacterial agents, underscoring the potential of computational approaches in therapeutic discovery. Glucomoringin Isothiocyanate (GMG-ITC) from Moringa oleifera Lam. is one of the phytochemical compounds with several biological activities, including antimicrobial, anti-inflammatory, and antioxidant activities, and is also effective against S. aureus. This study focuses on screening GMG-ITC as a potential drug candidate to combat MDR S. aureus infections through a molecular docking approach. Moreover, interaction amino acid analysis, in silico pharmacokinetics, compound target prediction, pathway enrichment analysis and molecular dynamics (MD) simulations were conducted for further investigation. Molecular docking and interaction analysis showed strong binding affinity towards S. aureus lipase, dihydrofolate reductase, and other MDR S. aureus proteins, including penicillin-binding protein 2a, MepR, D-Ala:D-Ala ligase, and RPP TetM, through hydrophilic and hydrophobic interactions. GMG-ITC also showed a strong binding affinity to cyclooxygenase-2 and FAD-dependent NAD(P)H oxidase, suggesting that it is a potential anti-inflammatory and antioxidant candidate that may eliminate inflammation and oxidative stress associated with S. aureus infections. MD simulations validated the stability of the GMG-ITC molecular interactions determined by molecular docking. In silico pharmacokinetic analysis highlights its potency as a drug candidate, showing strong absorption, distribution, and excretion properties in combination with low toxicity. It acts as an active protease and enzyme inhibitor with moderate activity against GPCR ligands, ion channels, nuclear receptor ligands, and kinases. Enrichment analysis further elucidated its involvement in important biological, molecular, and cellular functions with potential therapeutic applications in diseases like cancer, hepatitis B, and influenza. Results suggest that GMG-ITC is an effective antibacterial agent that could treat MDR S. aureus-associated infections.

• Klíčová slova
• GO and KEGG enrichment pathway, Glucomoringin isothiocyanate, In silico pharmacokinetic analysis, MD simulation, Molecular docking, Multi-drug resistance,
• MeSH
• antibakteriální látky * chemie   farmakologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   chemie   metabolismus   MeSH
• fytonutrienty chemie   farmakologie   MeSH
• isothiokyanatany * chemie   farmakologie   MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus účinky léků   MeSH
• mnohočetná bakteriální léková rezistence účinky léků   MeSH
• Moringa oleifera chemie   MeSH
• objevování léků MeSH
• počítačová simulace MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu * MeSH
• Staphylococcus aureus účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• bakteriální proteiny MeSH
• benzyl isothiocyanate MeSH Prohlížeč
• fytonutrienty MeSH
• isothiokyanatany * MeSH

Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching Cmax within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.

• Klíčová slova
• Acetylcholinesterase, Alzheimer's disease, Blood-brain-barrier, In silico metabolism prediction, Metabolism, Pharmacokinetics,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• akridiny MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• cholinesterasové inhibitory * farmakologie   MeSH
• myši MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Prohlížeč
• acetylcholinesterasa MeSH
• akridiny MeSH
• cholinesterasové inhibitory * MeSH

Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus-Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.

• Klíčová slova
• Golem, biorelevant, caffeine, dissolution, multivariate data analysis,
• MeSH
• biologické modely * MeSH
• design vybavení MeSH
• farmaceutická chemie * MeSH
• farmakokinetika * MeSH
• gastrointestinální absorpce MeSH
• gastrointestinální trakt metabolismus   MeSH
• multivariační analýza MeSH
• počítačová simulace MeSH
• rozpustnost * MeSH
• Publikační typ
• časopisecké články MeSH

ETHNOPHARMACOLOGICAL RELEVANCE: The development of selective inhibitors of monoamine oxidase B (MAO-B) has been essential in treating Parkinson's disease. However, the apparent hepatotoxicity and drug-drug interactions of current inhibitors accentuate the need for the development of novel pharmacotherapies. Crossyne guttata (L.) D. & U. Müll-Doblies is used frequently by Rastafarian bush doctors to treat alcoholism, a disorder which is also accentuated by MAO. OBJECTIVE: The study sought to isolate, identify and characterise the biologically active constituents of C. guttata based on their ability to inhibit the MAO enzymes. MATERIALS AND METHODS: Column chromatography was used to isolate the biologically active alkaloids of C. guttata. The ability of the alkaloids to inhibit the biotransformation of 4-aminoantipyrine by the MAO enzymes was evaluated in vitro. In silico docking was conducted using AutoDock Vina server while the pharmacokinetic properties of the compounds were evaluated using SwissADME. RESULTS: Chromatographic separation of an ethanolic fraction of C. guttata yielded the alkaloids crinamine 1 and epibuphanisine 2. 1 and 2 along with structurally related alkaloids haemanthamine 3 and haemanthidine 4 were evaluated for their ability to inhibit the action of isozymes of MAO in vitro. Alkaloids effected submicromolar IC50 values against MAO-B, the most potent of which being crinamine 1 (0.014 μM) > haemanthidine 4 (0.017 μM) > epibuphanisine 2 (0.039 μM) > haemanthamine 3 (0.112 μM). Binding energies of the alkaloids correlated well with their inhibitory potential with crinamine displaying the best binding efficacy and binding energy score with MAO-B. DISCUSSION AND CONCLUSION: Crinamine and epibuphanisine exhibited potent and selective inhibitory activity towards MAO-B. After comprehensive in silico investigations encompassing robust molecular docking analysis, the drug-like attributes and safety of the alkaloids suggest the crinamine is a potentially safe drug for human application.

• Klíčová slova
• Alkaloid, Crinamine, Crossyne guttata, Drug-likeness, Monoamine oxidase,
• MeSH
• alkaloidy amarylkovitých chemie   farmakokinetika   farmakologie   toxicita   MeSH
• bezpečnost pacientů MeSH
• biologické modely * MeSH
• Cercopithecus aethiops MeSH
• hodnocení rizik MeSH
• inhibitory MAO chemie   farmakokinetika   farmakologie   toxicita   MeSH
• konformace proteinů MeSH
• lidé MeSH
• monoaminoxidasa chemie   metabolismus   MeSH
• mutace MeSH
• Salmonella typhimurium účinky léků   genetika   MeSH
• simulace molekulového dockingu * MeSH
• Vero buňky MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• crinamine MeSH Prohlížeč
• inhibitory MAO MeSH
• monoaminoxidasa MeSH

BACKGROUND: Once-daily administration of aminoglykosides is routinely used, but comparative efficacy data for patients with cystic fibrosis are not available. METHODS AND RESULTS: The aim of the this study was to compare the predicted pharmacodynamic (PD) activity of amikacin at 28 mg/kg/den administered every 24 hod.(q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of the amikacin serum concentration from 42 CF children patients. Individual pharmacokinetics values were used to construct serum concentration--versus time curves and to determine various indices (c peak/MIC ratio and time during the concentration was less than the MIC--T < MIC) for all three dose regimens described above. MIC (minimal inhibitory concentration) for Pseudomonas aeruginosa was 4 mg/l. Significantly lower c peak/MIC but shorter T < MIC were noted when regimens of q8h versus q12h (p < 0.001), q8h vs. q24h (p < 0.001) and q12h vs. q24h (p < 0.001) were compared. This analysis suggests that the potential advantage of achieving a greater c peak/MIC with once-daily aminoglycoside administration may be neutralized by the significantly greater T < MIC in CF patients compared with that achieved with multiple-daily-dosing regimens. CONCLUSIONS: Routine use of once daily amikacin administration could not be recommended until the clinical data confirming efficiency of this dose modality are available.

• MeSH
• amikacin aplikace a dávkování   farmakokinetika   MeSH
• antibakteriální látky aplikace a dávkování   farmakokinetika   MeSH
• biologické modely MeSH
• cystická fibróza krev   mikrobiologie   MeSH
• dítě MeSH
• infekce dýchací soustavy komplikace   farmakoterapie   MeSH
• lidé MeSH
• mladiství MeSH
• počítačová simulace MeSH
• pseudomonádové infekce komplikace   farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amikacin MeSH
• antibakteriální látky MeSH

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

• Klíčová slova
• MD simulation, SARS-CoV-2, docking, drug, main protease, triazole,
• MeSH
• antivirové látky chemie   metabolismus   terapeutické užití   MeSH
• benzocyklohepteny chemie   metabolismus   MeSH
• chemické databáze MeSH
• COVID-19 virologie   MeSH
• farmakoterapie COVID-19 MeSH
• inhibitory proteas chemie   metabolismus   terapeutické užití   MeSH
• koronavirové proteasy 3C antagonisté a inhibitory   metabolismus   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• ligandy MeSH
• poločas MeSH
• SARS-CoV-2 enzymologie   izolace a purifikace   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• triazoly chemie   metabolismus   terapeutické užití   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3C-like proteinase, SARS-CoV-2 MeSH Prohlížeč
• antivirové látky MeSH
• bemcentinib MeSH Prohlížeč
• benzocyklohepteny MeSH
• inhibitory proteas MeSH
• koronavirové proteasy 3C MeSH
• ligandy MeSH
• triazoly MeSH

In silico methods like molecular docking and pharmacophore modeling are established strategies in lead identification. Their successful application for finding new active molecules for a target is reported by a plethora of studies. However, once a potential lead is identified, lead optimization, with the focus on improving potency, selectivity, or pharmacokinetic parameters of a parent compound, is a much more complex task. Even though in silico molecular modeling methods could contribute a lot of time and cost-saving by rationally filtering synthetic optimization options, they are employed less widely in this stage of research. In this review, we highlight studies that have successfully used computer-aided SAR analysis in lead optimization and want to showcase sound methodology and easily accessible in silico tools for this purpose.

• Klíčová slova
• Docking, Lead optimization, Molecular modeling, Pharmacophore modeling, Structure-activity relationship,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: One of the main obstacles for reliable quantitative dynamic contrast-enhanced (DCE) MRI is the need for accurate knowledge of the arterial input function (AIF). This is a special challenge for preclinical small animal applications where it is very difficult to measure the AIF without partial volume and flow artifacts. Furthermore, using advanced pharmacokinetic models (allowing estimation of blood flow and permeability-surface area product in addition to the classical perfusion parameters) poses stricter requirements on the accuracy and precision of AIF estimation. This paper addresses small animal DCE-MRI with advanced pharmacokinetic models and presents a method for estimation of the AIF based on blind deconvolution. METHODS: A parametric AIF model designed for small animal physiology and use of advanced pharmacokinetic models is proposed. The parameters of the AIF are estimated using multichannel blind deconvolution. RESULTS: Evaluation on simulated data show that for realistic signal to noise ratios blind deconvolution AIF estimation leads to comparable results as the use of the true AIF. Evaluation on real data based on DCE-MRI with two contrast agents of different molecular weights showed a consistence with the known effects of the molecular weight. CONCLUSION: Multi-channel blind deconvolution using the proposed AIF model specific for small animal DCE-MRI provides reliable perfusion parameter estimates under realistic signal to noise conditions.

• Klíčová slova
• Arterial input function, Blind deconvolution, DCE-MRI,
• MeSH
• algoritmy MeSH
• arterie diagnostické zobrazování   MeSH
• farmakokinetika MeSH
• kontrastní látky farmakokinetika   MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nekróza patologie   MeSH
• perfuze MeSH
• počítačová simulace MeSH
• počítačové zpracování obrazu metody   MeSH
• poměr signál - šum MeSH
• regresní analýza MeSH
• reprodukovatelnost výsledků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kontrastní látky MeSH

PURPOSE: The Tofts and the extended Tofts models are the pharmacokinetic models commonly used in dynamic contrast-enhanced MRI (DCE-MRI) perfusion analysis, although they do not provide two important biological markers, namely, the plasma flow and the permeability-surface area product. Estimates of such markers are possible using advanced pharmacokinetic models describing the vascular distribution phase, such as the tissue homogeneity model. However, the disadvantage of the advanced models lies in biased and uncertain estimates, especially when the estimates are computed voxelwise. The goal of this work is to improve the reliability of the estimates by including information from neighboring voxels. THEORY AND METHODS: Information from the neighboring voxels is incorporated in the estimation process through spatial regularization in the form of total variation. The spatial regularization is applied on five maps of perfusion parameters estimated using the tissue homogeneity model. Since the total variation is not differentiable, two proximal techniques of convex optimization are used to solve the problem numerically. RESULTS: The proposed algorithm helps to reduce noise in the estimated perfusion-parameter maps together with improving accuracy of the estimates. These conclusions are proved using a numerical phantom. In addition, experiments on real data show improved spatial consistency and readability of perfusion maps without considerable lowering of the quality of fit. CONCLUSION: The reliability of the DCE-MRI perfusion analysis using the tissue homogeneity model can be improved by employing spatial regularization. The proposed utilization of modern optimization techniques implies only slightly higher computational costs compared to the standard approach without spatial regularization.

• Klíčová slova
• DCE-MRI, perfusion parameter estimation, proximal methods, spatial regularization, tissue homogeneity model, total variation,
• MeSH
• algoritmy MeSH
• fantomy radiodiagnostické MeSH
• glioblastom diagnostické zobrazování   MeSH
• kontrastní látky farmakologie   MeSH
• krysa rodu Rattus MeSH
• magnetická rezonanční tomografie * MeSH
• mozek diagnostické zobrazování   MeSH
• nádory mozku diagnostické zobrazování   MeSH
• perfuze MeSH
• permeabilita MeSH
• počítačová simulace MeSH
• počítačové zpracování obrazu MeSH
• poměr signál - šum MeSH
• reprodukovatelnost výsledků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kontrastní látky MeSH