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Journal of Molecular Graphics &... Jul 2023An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel... (Review)
Review
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Alzheimer Disease; Molecular Docking Simulation; Diflunisal; Drug Repositioning; Reproducibility of Results; Cholinesterase Inhibitors; Acetylcholinesterase
PubMed: 37087882
DOI: 10.1016/j.jmgm.2023.108471 -
Antibiotics (Basel, Switzerland) Jul 2023Invasive methicillin-resistant (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional...
Invasive methicillin-resistant (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection.
PubMed: 37508276
DOI: 10.3390/antibiotics12071180 -
Orphanet Journal of Rare Diseases May 2024There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers....
BACKGROUND
There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy.
OBJECTIVES
To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy.
METHODS
We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality.
RESULTS
One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21).
CONCLUSIONS
While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.
Topics: Humans; Amyloid Neuropathies, Familial; Male; Female; Retrospective Studies; Aged; Middle Aged; Cohort Studies; Prealbumin; Aged, 80 and over; Adult
PubMed: 38720335
DOI: 10.1186/s13023-024-03198-7 -
ESC Heart Failure Feb 2024We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In...
AIMS
We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.
METHODS AND RESULTS
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t = 21 h) and the TTRA81V homozygote protein (t = 17.5 h). The kinetic stability fell between that of the TTRWT (t = 42 h) and the early-onset TTRL55P mutation (t = 4.4 h), indicating the patient's late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient's serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).
CONCLUSIONS
We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.
Topics: Male; Humans; Aged, 80 and over; Prealbumin; Contrast Media; Stroke Volume; Gadolinium; Ventricular Function, Left; Amyloid Neuropathies, Familial; Cardiomyopathies; Mutation
PubMed: 37827496
DOI: 10.1002/ehf2.14543 -
Revista Espanola de Cardiologia... May 2024
Topics: Humans; Amyloid Neuropathies, Familial; Diflunisal; Male; Cardiomyopathies; Female; Aged; Treatment Outcome; Middle Aged
PubMed: 38325700
DOI: 10.1016/j.rec.2023.10.016 -
Molecules (Basel, Switzerland) Jan 2024The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of...
The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer's Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with F. [F/F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.
Topics: Humans; Animals; Mice; Pharmaceutical Preparations; Tissue Distribution; Alzheimer Disease; Prealbumin; Amyloid beta-Peptides; Excipients; Diflunisal
PubMed: 38257401
DOI: 10.3390/molecules29020488