RESUMO
Sulphotransferases (SULTs) are a major phase II metabolic enzyme class contributing ~20 % to the Phase II metabolism of FDA-approved drugs. Ignoring the potential for SULT-mediated metabolism leaves a strong potential for drug-drug interactions, often causing late-stage drug discovery failures or black-boxed warnings on FDA labels. The existing models use only accessibility descriptors and machine learning (ML) methods for class and site of sulfonation (SOS) predictions for SULT. In this study, a variety of accessibility, reactivity, and hybrid models and algorithms have been developed to make accurate substrate and SOS predictions. Unlike the literature models, reactivity parameters for the aliphatic or aromatic hydroxyl groups (R/Ar-O-H), the Bond Dissociation Energy (BDE) gave accurate models with a True Positive Rate (TPR)=0.84 for SOS predictions. We offer mechanistic insights to explain these novel findings that are not recognized in the literature. The accessibility parameters like the ratio of Chemgauss4 Score (CGS) and Molecular Weight (MW) CGS/MW and distance from cofactor (Dis) were essential for class predictions and showed TPR=0.72. Substrates consistently had lower BDE, Dis, and CGS/MW than non-substrates. Hybrid models also performed acceptablely for SOS predictions. Using the best models, Algorithms gave an acceptable performance in class prediction: TPR=0.62, False Positive Rate (FPR)=0.24, Balanced accuracy (BA)=0.69, and SOS prediction: TPR=0.98, FPR=0.60, and BA=0.69. A rule-based method was added to improve the predictive performance, which improved the algorithm TPR, FPR, and BA. Validation using an external dataset of drug-like compounds gave class prediction: TPR=0.67, FPR=0.00, and SOS prediction: TPR=0.80 and FPR=0.44 for the best Algorithm. Comparisons with standard ML models also show that our algorithm shows higher predictive performance for classification on external datasets. Overall, these models and algorithms (SOS predictor) give accurate substrate class and site (SOS) predictions for SULT-mediated Phase II metabolism and will be valuable to the drug discovery community in academia and industry. The SOS predictor is freely available for academic/non-profit research via the GitHub link.
RESUMO
This study aimed to explore extrusion three dimensional (3D) printing technology to develop praziquantel (PZQ)-loaded minicaplets and evaluate their in vitro and in vivo delivery capabilities. PZQ-loaded minicaplets were 3D printed using a fused deposition modelling (FDM) principle-based extrusion 3D printer and were further characterized by different in vitro physicochemical and sophisticated analytical techniques. In addition, the % PZQ entrapment and in vitro PZQ release performance were evaluated using chromatographic techniques. It was in vitro observed that PZQ was fully released in the gastric pH medium within the period of gastric emptying, that is, 120 min, from the PZQ-loaded 3D printed minicaplets. Furthermore, in vivo pharmacokinetic (PK) profiles of PZQ-loaded 3D printed minicaplets were systematically evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The PK profile of the PZQ-loaded 3D printed minicaplets was established using different parameters such as Cmax, Tmax, AUC0-t, AUC0-∞, and oral relative bioavailability (RBA). The Cmax value of pristine PZQ was found at 64.79 ± 13.99 ng/ml, while PZQ-loaded 3D printed minicaplets showed a Cmax of 263.16 ± 47.85 ng/ml. Finally, the PZQ-loaded 3D printed minicaplets showed 9.0-fold improved oral RBA compared with that of pristine PZQ (1.0-fold). Together, these observations potentiate the desired in vitro and improved in vivo delivery capabilities of PZQ from the PZQ-loaded 3D printed minicaplets.
Assuntos
Praziquantel , Espectrometria de Massas em Tandem , Praziquantel/química , Cromatografia Líquida , Impressão Tridimensional , Disponibilidade Biológica , Liberação Controlada de Fármacos , Tecnologia Farmacêutica/métodos , ComprimidosRESUMO
Phlogacanthus thyrsiformis (P. thyrsiformis) is a non-conventional edible plant that has been used as a vegetable and as a traditional medicine to treat various diseases. This non-conventional edible plant is widespread in India, Yunnan-Chinese provinces, and Vietnam. Despite this potential claim, the phytochemical investigation of plants remains incomplete. In the present study, the chemical profile analysis of P. thyrsiformis leaves extracts was performed using LC-ESI-QTOF-MS/MS and GC/QTOF-MS and assessed for its antioxidants and enzyme inhibitory potential. A cursory examination of the phytometabolites of different solvents extracts revealed chloroform extract has different metabolites, including phenols, terpenes, glycosides and alkaloids. 113 and 138 metabolites, including primary and secondary metabolites, were identified using LC-ESI-QTOF-MS/MS and GC/QTOF-MS, respectively. Total phenolic content was observed highest in chloroform extract (60.59 ± 1.25 mg GAE/g). Maximum antioxidant activity was found to be in chloroform extract, which was identified by DPPH (0.88 ± 0.29 mg/mL), ABTS (0.54 ± 0.1 mg/mL) and FRAP assay (26.46 ± 1.65 mg AA/g extract). Ethyl acetate extract have the highest α-amylase (0.09 ± 0.11 mg/mL) and α-glucosidase (0.088 ± 0.13 mg/mL) enzyme inhibition potential. For all the detected molecules, docking and molecular dynamics studies were performed. To the best of our knowledge, this is the first report that discusses LC-ESI-QTOF-MS/MS and GC/QTOF-MS-based metabolites profiling of P. thyrsiformis that can help to treat various diseases.
Assuntos
Antioxidantes , Espectrometria de Massas em Tandem , Antioxidantes/química , Antioxidantes/farmacologia , China , Clorofórmio/análise , Glicosídeos , Fenóis/análise , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Solventes/química , Terpenos/análise , alfa-Amilases , alfa-GlucosidasesRESUMO
OBJECTIVES: 3D printed polymeric film intended for topical delivery of berberine (BBR) was developed using stereolithography (SLA) to enhance its local concentrations. PEGDMA was utilized as photopolymerizing resin, with PEG 400 as an inert component to facilitate BBR solubilization and permeation. METHODS: Three batches of topical films were printed by varying resin and PEG 400 compositions. In-vitro physicochemical characterizations of the 3D printed films were performed using several analytical techniques including ex-vivo drug permeation studies. In-vivo skin irritation studies were also conducted to assess the skin irritation potential. KEY FINDINGS: Films were 3D printed according to design specifications with minimal variations. Microscopic analysis confirmed 3D architecture, while thermal and X-ray diffraction studies revealed amorphous BBR entrapment. Drug permeation study showed effective ex-vivo diffusion up to 344.32 ± 61.20 µg/cm2 after 24.0 h possessing a higher ratio of PEG 400. In-vivo skin irritation studies have suggested the non-irritant nature of printed films. CONCLUSIONS: Results indicated the suitability of SLA 3D printing for topical application in the treatment of skin diseases. The presence of PEG 400 in the printed 3D films facilitated BBR diffusion, resulting in an improved flux in ex-vivo model and non-irritant properties in vivo.
Assuntos
Berberina , Estereolitografia , Polietilenoglicóis , Polímeros/química , Impressão TridimensionalRESUMO
The selection of an appropriate matrix for the preparation of amorphous extrudate in hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Therefore, it is necessary to have an appropriate knowledge of drug-polymer miscibility, the interaction between the drug-polymer on mixing, and Gibb's free thermal energy of mixing to screen polymers through thermodynamic phase diagrams, to be suitable amorphous matrix system for HME. Here, we evaluated the possibility of three different polymers, namely, Eudragit®EPO, polyvinyl alcohol (PVA), Kollicoat®IR (KIR) with Praziquantel (PZQ), with proper validation of the Flory-Huggins theory and construction of the phase diagram using the melting point depression approach to determine a suitable matrix for HME. The solubility parameter theoretical calculation approach was used as a preliminary study to validate the miscibility of PZQ with three different polymers. Theoretical and experimental validation studies using the Flory-Huggins interaction parameter value using the melting point depression approach and the effect of PZQ loading on the interaction parameter were systematically validated to predict thermodynamic phase diagrams and Gibbs free energy of mixing for screening these polymers for the preparation of amorphous extrudate. Using the phase diagram, the thermal processing temperature for the HME was determined using a T-φ phase diagram to obtain an appropriate matrix. The obtained extrudates were further validated through physical appearance, microscopic structure, thermal and functional group characterizations, followed by the PZQ assay. Thus, considering the solid-state properties, the processing parameters of HME were selected to obtain stable extrudates and an appropriate matrix for PZQ loading.
Assuntos
Polímeros , Praziquantel , Química Farmacêutica , Composição de Medicamentos , Tecnologia de Extrusão por Fusão a Quente , Temperatura Alta , SolubilidadeRESUMO
The stems of Boswellia ovalifoliolata BAL. & HENRY (Burseraceae) afforded two new macrocyclic diaryl ether heptanoids, ovalifoliolatin A (1) and B (2) together with three known compounds; acerogenin C (3), 3 alpha-hydroxyurs-12-ene (4), and sitost-4-en-3-one (5). The structures were established by means of spectroscopic analysis and compounds 1, 3-5 were evaluated for their antibacterial activity.