OBJECTIVETo predict the percutaneous drug permeability coefficients with modified regression equation.

METHODSThe semiempirical self-consistent field molecular orbital calculation AM1 method was used to calculate the quantum chemical parameters and the modified theoretical linear solvation energy relationship was used to obtain the regression equation of the permeability coefficients of drugs through human epidermis.

RESULTThe permeability coefficients (P) of 36 nonelectrolytes were well linearly correlated with their theoretical descriptors including molecular volume (V), hydrogen bond acidity (sum alpha(2)(H)), hydrogen bond basicity (sum beta(2)(H)) and polarizability index (pi(1)). The regression equation was logP=-6.790+1.571 V+0.1550 pi(1)-1.295 sum alpha(2)(H)-2.485 sum beta(2)(H)(n=36,r=0.9777).

CONCLUSIONThe modified theoretical linear solvation energy relationship can be used to predict the skin permeability of drugs.

Humans ; Hydrogen Bonding ; Models, Theoretical ; Permeability ; Regression Analysis ; Skin Absorption

OBJECTIVETo predict in vivo human skin permeability of drugs.

METHODSAppropriate BP(Back-propagation) neural network to predict human skin permeation ratios of drugs (R, absorbed/unabsorbed) was established. The octanol water partition coefficients (logP), molecular volumes (V), hydrogen bond acidities (sigma alpha 2(H)) and hydrogen bond basidities (sigma beta 2(H)) were selected as the neural units of input layer, and logR values were selected as the neural units of output layer.

RESULTSThe calculated logR values of 17 drugs were in good accordance with their observed values.

CONCLUSIONBP neural network can be used to predict in vivo human skin permeability of drugs.

Humans ; Hydrogen Bonding ; Neural Networks (Computer) ; Permeability ; Skin Absorption ; Solubility

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.
Carboxylesterase/metabolism* ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions

Zearalenone is one of the most widely polluted Fusarium toxins in the world, seriously endangering livestock and human health. Zearalenone hydrolase (ZHD) derived from Clonostachys rosea can effectively degrade zearalenone. However, the high temperature environment in feed processing hampers the application of this enzyme. Structure-based rational design may provide guidance for engineering the thermal stability of enzymes. In this paper, we used the multiple structure alignment (MSTA) to screen the structural flexibility regions of ZHD. Subsequently, a candidate mutation library was constructed by sequence conservation scoring and conformational free energy calculation, from which 9 single point mutations based on residues 136 and 220 were obtained. The experiments showed that the thermal melting temperature (T_m) of the 9 mutants increased by 0.4-5.6 ℃. The S220R and S220W mutants showed the best thermal stability, the T_m of which increased by 5.6 ℃ and 4.0 ℃ compared to that of the wild type. Moreover, the thermal half-inactivation time at 45 ℃ were 15.4 times and 3.1 times longer, and the relative activities were 70.6% and 57.3% of the wild type. Molecular dynamics simulation analysis showed that the interaction force at and around the mutation site was enhanced, contributing to the improved thermal stability of ZHD. The probability of 220-K130 hydrogen bond of the mutants S220R and S220W increased by 37.1% and 19.3%, and the probability of K130-D223 salt bridge increased by 30.1% and 12.5%, respectively. This work demonstrated the feasibility of thermal stability engineering strategy where the structural and sequence alignment as well as free energy calculation of natural enzymes were integrated, and obtained ZHD variants with enhanced thermal stability, which may facilitate the industrial application of ZHD.
Humans ; Hydrolases ; Zearalenone ; Trichothecenes ; Gene Library ; Hydrogen Bonding

Objectives: This study aims to assess the drug-likeness and binding of nucleobase-substituted ponatinib analogues towards wild-type and T315I mutant BCR-ABL tyrosine kinases. Methodology: A total of 415 ponatinib analogues, encompassing single and combinatorial modifications on five parts of the drug were generated, profiled in SwissADME, and subjected to molecular docking using AutoDock4. Complexes formed by the top analogues then underwent a 100-ns molecular dynamics simulation with GROMACS. Results: Analogues featuring the replacement of the imidazo[1,2b]pyridazine with adenine and cytosine exhibited promising binding free energies, attributed to the presence of primary amines that facilitate crucial hydrogen bond interactions in the hinge region. RMSD, RMSF, and atomic distance analyses of the MD trajectories revealed that the six top analogues formed stable complexes in their inactive DFG-out conformations. Changes in the MMPBSA and MMGBSA-calculated free energies were mainly driven by changes in hydrogen bonds. Furthermore, drug-likeness predictions supported the formulation of most analogues for oral administration. Conclusion Among the top analogues, VP10004 and VP81014 exhibited the most favorable binding free energies and interactions with the target models, while VP10312 was identified as the most feasible candidate for synthesis.
Hydrogen Bonding ; Molecular Dynamics Simulation ; Molecular Docking Simulation

PURPOSE: This study examined the recovery of the dentin-resin bonding strength, and the difference in the bonding strength after applying pH hemostatic agents at various pH. MATERIALS AND METHODS: Bosmin, Hemodent, Astregedent, and Visine were used as the hemostatic agents in this study. The Bosmin, Hemodent, and Astrigedent hemostatic agents are acidic, and the Visine hemostatic agent is neutral and is used as a decongestant. Ninety human molar teeth were used as the specimen. The teeth were sectioned using a diamond wheel until the dentin was exposed and wet ground by silica paper. The specimens were divided into two groups according to the hemostatic agent used. The specimens were then subdivided into 9 groups according to the application of re etching (R group) or rinsing only (N group). A commonly used resin bonding procedure was used in the control group. The resin bonding procedure was managed dentin using celluloid capsule. In addition, the shear bond strength was measured using an Instron. RESULTS: In general, samples with the applied hemostatic agent, with the exception of Visine, had a slightly weak bond that was similar to the control group. In addition, the rinsing only (N) group had slightly weak bond that was similar to the re etching (R) group. CONCLUSION: The application of a hemostatic agent on the dentin surface does not affect the shear bond strength after application for a short time. In addition, rinsing only can recover the shear bond strength making other management procedures redundant, particularly re etching.
Dentin ; Dentin-Bonding Agents ; Diamond ; Humans ; Hydrogen-Ion Concentration ; Imidazoles ; Molar ; Silicon Dioxide ; Tooth

PURPOSE: This study aimed to investigate the efficacy of cleaning solutions on saliva-contaminated zirconia in comparison to air-abrasion in terms of resin bonding. MATERIALS AND METHODS: For saliva-contaminated airabraded zirconia, seven cleaning methods)-no contamination (NC), water-spray rinsing (WS), additional airabrasion (AA), and cleaning with four solutions (Ivoclean [IC]; 1.0 wt% sodium dodecyl sulfate [SDS], 1.0 wt% hydrogen peroxide [HP], and 1.0 wt% sodium hypochlorite [SHC])-were tested. The zirconia surfaces for each group were characterized using various analytical techniques. Three bonded resin (Panavia F 2.0) cylinders (bonding area: 4.5 mm2) were made on one zirconia disk specimen using the Ultradent jig method [four disks (12 cylinders)/group; a total of 28 disks]. After 5,000 thermocycling, all specimens were subjected to a shear bond strength test with a crosshead speed of 1.0 mm/minute. The fractured surfaces were observed using an optical and scanning electron microscope (SEM). RESULTS: Contact angle measurements showed that groups NC, AA, IC, and SHC had hydrophilic surfaces. The X-ray photoelectron spectroscopy (XPS) analysis showed similar elemental distributions between group AA and groups IC and SHC. Groups IC and SHC showed statistically similar bond strengths to groups NC and AA (P>.05), but not groups SDS and HP (P<.05). For groups WS, SDS, and HP, blister-like bubble formations were observed on the surfaces under SEM. CONCLUSION: Within the limitations of this in vitro study, some of the cleaning solutions (IC or SHC) were effective in removing saliva contamination and enhancing the resin bond strength.
Dental Bonding ; Hydrogen Peroxide ; Photoelectron Spectroscopy ; Saliva ; Sodium Dodecyl Sulfate ; Sodium Hypochlorite

OBJECTIVETo prepare a new synthetic macromolecular resin class of denture adhesive (named Comfort-DA).

METHODSTwelve different formulae for denture adhesive were designed by orthogonal design. Each factor affecting tensile bond strength of adhesive was analyzed by ANNOVA to select the best formula. Then the chemical and physical properties, such as tensile bond strength, pH value, and viscosity, were evaluated and compared with Fittydent in vitro also.

RESULTSThe effect of content of polyvinyl acetate and cellulose ether on tensile bond strength exhibited no statistical significance (P > 0.05), while ethyl alcohol and CMC-Na showed statistical significance and mutual action (P < 0.05). Results of testing viscosity and shearing stress showed that there was no significant difference between Fittydent and Comfort-DA (P > 0.05), while Fittydent exhibited a significantly lower tensile bond strength than the prepared one (P < 0.05). The prepared adhesive demonstrated a neutral or slightly basic pH.

CONCLUSIONSThe generally favorable in vitro performance of the prepared adhesive (Comfort-DA) formulation indicated that it might be efficacious denture adhesive.

Adhesives ; chemistry ; Composite Resins ; chemistry ; Dental Bonding ; Denture Retention ; methods ; Humans ; Hydrogen-Ion Concentration ; Tensile Strength

Heart ; drug effects ; Heart Failure ; drug therapy ; Humans ; Hydrogen Bonding ; Nitrogen Oxides ; pharmacology ; therapeutic use

Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by "pull-and-contact" with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.
Binding Sites ; Capsaicin ; chemistry ; pharmacokinetics ; Humans ; Hydrogen Bonding ; Protein Binding ; TRPV Cation Channels ; chemistry ; genetics ; metabolism