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SAR and QSAR in Environmental Research Jun 2024Neurodegenerative diseases lead to a gradual decline in cognitive and motor functions due to the progressive loss of neurons in the central nervous system. The role of...
Neurodegenerative diseases lead to a gradual decline in cognitive and motor functions due to the progressive loss of neurons in the central nervous system. The role of dual leucine zipper kinase (DLK) in regulating stress responses and neuronal death pathways highlights its significance as a target against neurodegenerative diseases. The non-availability of FDA-approved drugs emphasizes a need to identify novel DLK-inhibitors. We screened NPAtlas (Natural products) and MedChemExpress (FDA-approved) libraries to identify potent ATP-competitive DLK inhibitors. ADMET analyses identified four compounds (two natural products and two FDA-approved) with favourable features. Subsequently, we performed molecular dynamics simulations to examine the binding-stability and ligand-induced conformational dynamics. Molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations demonstrated CID139591660, dithranol, and danthron having greater affinity, while CID156581477 showed lower affinity than control sunitinib. PCA and network analysis results indicated structural and network alteration post-ligand binding. Furthermore, we identified an analogue of CID156581477 using the deep learning-based web server DeLA Drug which demonstrated a higher affinity than its parent compound and the control and identified several crucial interacting residues. Overall, our study provides significant theoretical guidance for designing potent novel DLK inhibitors and compounds that could emerge as promising drug candidates against DLK following laboratory validation.
PubMed: 38855951
DOI: 10.1080/1062936X.2024.2363195 -
International Journal of Pharmaceutics Dec 2020The paper concerns the modelling of the passive solute transport through porous membranes. A general scheme for the mass transport has been developed upon the mixed...
The paper concerns the modelling of the passive solute transport through porous membranes. A general scheme for the mass transport has been developed upon the mixed diffusion-advection-reaction model. The passive advection has been introduced as a certain simplification of the Navier-Stokes problem, involving a pressure gradient-induced creeping flow of an incompressible Newtonian fluid. Nine scenarios for the drug transport process have been tested versus two experimental datasets acquired earlier (photoacoustic depth-profiling and contact angle surface wettability techniques) for the characterization of bulk and interfacial processes in a model pharmaceutical system: the synthetic dodecanol-collodion porous membrane in contact with a photodegradable pigment dithranol. The scenarios considered include three mass transport models (the diffusion-advection-reaction, diffusion-advection and diffusion-reaction models) under three distinct types of the lower (the donor/acceptor interface) boundary conditions: the Dirichlet-type instantaneous source, the Dirichlet-type interface relaxation, and the Neumann-type concentration gradient. The results obtained indicate a considerable agreement between the experimental data and predictions of the diffusion-reaction and the general models for long times, however, some deviations were exhibited at the initial stages of the permeation process. It is considered, that the discrepancies originate from a specific penetrant behaviour at the interfaces, which violates boundary transfer schemes classically employed for the mass transport phenomena quantification. Moreover, an additional mixing process taking place close to the interface related to the liquid flow driven by the surface tension gradients (so-called classic and thermal Marangoni effect) could play a still underestimated role in the trans-interfacial mass transport.
Topics: Administration, Cutaneous; Biological Transport; Diffusion; Porosity; Solutions
PubMed: 33122112
DOI: 10.1016/j.ijpharm.2020.120017