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Pharmaceutics Jan 2022A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The...
A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.
PubMed: 35213988
DOI: 10.3390/pharmaceutics14020255 -
Cancer Medicine Nov 2019Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key...
BACKGROUND
Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment.
METHODS
We used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case-control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning.
RESULTS
The regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival.
CONCLUSION
Using an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.
Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Case-Control Studies; Drug Repositioning; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; Phenotype; Prognosis; Survival Analysis; Transcription Factors
PubMed: 31503425
DOI: 10.1002/cam4.2493 -
Frontiers in Microbiology 2020The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment...
The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well , most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5-2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant ( < 0.0001) activity against a strain compared with the vehicle, in an wound infection model. However, both and analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.
PubMed: 33101232
DOI: 10.3389/fmicb.2020.560798 -
Antimicrobial Agents and Chemotherapy Mar 2020Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some...
Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on , reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against but also against some spp., in particular against In parallel, we identified drugs that had antifungal activity against and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.
Topics: Amphotericin B; Animals; Antifungal Agents; Auranofin; Candida albicans; Candidiasis; Cell Line; Ciclopirox; Cryptococcosis; Cryptococcus neoformans; Drug Evaluation, Preclinical; Drug Repositioning; Drug Synergism; Erythromycin; Flucytosine; Humans; Mice; Microbial Sensitivity Tests; Opportunistic Infections; RAW 264.7 Cells; Zebrafish
PubMed: 31988099
DOI: 10.1128/AAC.01921-19