Monoamine Oxidase B Inhibitor Research Articles

Target Fisher: a Consensus Structure-Based Target Prediction Tool, and its Application in the Discovery of Selective MAO-B Inhibitors.

In this work we introduce Target Fisher, a consensus structure-based target prediction tool that integrates molecular docking and machine learning with the aim to aid in the identification of potential biological targets and the optimization of the use of bioassays. Target Fisher uses per-residue energy decomposition profiles extracted from docking poses as fingerprints to train target-specific machine learning models. It provides predictions for a curated set of 37 protein targets, covering a diverse range of biological entities, and offers a user-friendly interface accessible via a web server (https://gqc.quimica.unlp.edu.ar/targetfisher/). In this sense, Target Fisher is a valuable tool to aid organic and medicinal chemistry groups in target identification, drug discovery and drug repurposing. As a case study, we demonstrate the efficacy of Target Fisher by screening a small library of assorted natural products for targets relevant to neurodegenerative diseases, which resulted in the identification and experimental validation of selective inhibitors of monoamine oxidase B (MAO-B).

Identification of high-affinity Monoamine oxidase B inhibitors for depression and Parkinson's disease treatment: bioinformatic approach of drug repurposing.

Depression and Parkinson's disease (PD) are devastating psychiatric and neurological disorders that require the development of novel therapeutic interventions. Drug repurposing targeting predefined pharmacological targets is a widely use approach in modern drug discovery. Monoamine oxidase B (MAO-B) is a critical protein implicated in Depression and PD. In this study, we undertook a systematic exploration of repurposed drugs as potential inhibitors of MAO-B. Exploring a library of 3,648 commercially available drug molecules, we conducted virtual screening using a molecular docking approach to target the MAO-B binding pocket. Two promising drug molecules, Brexpiprazole and Trifluperidol, were identified based on their exceptional binding potential and drug profiling. Subsequently, all-atom molecular dynamics (MD) simulations were performed on the MAO-B-ligand complexes for a trajectory of 300 nanoseconds (ns). Simulation results demonstrated that the binding of Brexpiprazole and Trifluperidol induced only minor structural alterations in MAO-B and showed significant stabilization throughout the simulation trajectory. Overall, the finding suggests that Brexpiprazole and Trifluperidol exhibit strong potential as repurposed inhibitors of MAO-B that might be explored further in experimental investigations for the development of targeted therapies for depression and PD.

Computational exploration of acefylline derivatives as MAO-B inhibitors for Parkinson's disease: insights from molecular docking, DFT, ADMET, and molecular dynamics approaches.

Monoamine oxidase B (MAO-B) plays a pivotal role in the deamination process of monoamines, encompassing crucial neurotransmitters like dopamine and norepinephrine. The heightened interest in MAO-B inhibitors emerged after the revelation that this enzyme could potentially catalyze the formation of neurotoxic compounds from endogenous and exogenous sources. Computational screening methodologies serve as valuable tools in the quest for novel inhibitors, enhancing the efficiency of this pursuit. In this study, 43 acefylline derivatives were docked against the MAO-B enzyme for their chemotherapeutic potential and binding affinities that yielded GOLD fitness scores ranging from 33.21 to 75.22. Among them, five acefylline derivatives, namely, MAO-B14, MAO-B15, MAO-B16, MAO-B20, and MAO-B21, displayed binding affinities comparable to the both standards istradefylline and safinamide. These derivatives exhibited hydrogen-bonding interactions with key amino acids Phe167 and Ile197/198, suggesting their strong potential as MAO-B inhibitors. Finally, molecular dynamics (MD) simulations were conducted to evaluate the stability of the examined acefylline derivatives over time. The simulations demonstrated that among the examined acefylline derivatives and standards, MAO-B21 stands out as the most stable candidate. Density functional theory (DFT) studies were also performed to optimize the geometries of the ligands, and molecular docking was conducted to predict the orientations of the ligands within the binding cavity of the protein and evaluate their molecular interactions. These results were also validated by simulation-based binding free energies via the molecular mechanics energies combined with generalized Born and surface area solvation (MM-GBSA) method. However, it is necessary to conduct in vitro and in vivo experiments to confirm and validate these findings in future studies.

Living with Parkinson's disease in Portugal: Findings from PRISM study

BackgroundParkinson's disease (PD) ranks second in global neurodegenerative disorders. The “Parkinson's Real-world Impact assesSMent (PRISM)” study addressed the disease burden and treatment of European PD patients. Yet, the burden on Portuguese PD patients remains unexplored. Here, we outline the demographics, clinical features, and impact of PD in the Portuguese PRISM cohort. MethodsDescriptive analysis of the PRISM Portuguese cohort (80 patients) was performed, emphasizing socio-demographic data, anti-PD medication usage, PD impact on patients' lives and healthcare resources utilization. ResultsThe predominant comorbidities in the Portuguese PD cohort (55 % male; mean age 66.2 years; mean disease duration 8.8 years) included depression (26.3 %) and anxiety (26.3 %). Levodopa was the initial prescribed anti-PD medication for 88 % of patients. Among Portuguese PDP, dopamine agonists (DA), monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors were used by 50 %, 44.4 %, and 18.3 %, respectively. Portuguese PDP experienced impaired quality of life (PDQ-39 score: 31.3 ± 16.8), various non-motor symptoms, namely sadness/blues (65.4 %), urinary urgency (63.5 %), high/low sex interest (57.7 %), while 56 % reported at least one impulse control behavior. Additionally, 30.8 % retired early due to PD and 31.8 % reduced hours in daily activities. Mental health appointments were attended by 31 %, primarily in psychiatry (19 %) and psychology (6 %), and psychotherapy. ConclusionThis study uncovers the burden of PD among Portuguese patients, revealing current treatment methods, impact on daily life and healthcare resources employed in Portugal. It emphasizes the need for personalized clinical strategies at national and international levels to improve long-term health outcomes and quality of life of PD patients.

Effect of halogens on 3-[4-(dimethylamino) phenyl]-1-phenylprop-2-en-1-ones: development of a new class of monoamine oxidase-B inhibitors

Five dimethylamino-based chalcone derivatives (AC) were synthesized and evaluated for their inhibition degree against monoamine oxidase (MAO) enzymes. All AC compounds showed better inhibitory activity against MAO-B than that against MAO-A. AC4 showed the highest inhibitory ability with an IC50 value of 0.020 µM, similar to that of a reference drug safinamide (IC50 = 0.019 µM) against MAO-B, followed by AC1 (IC50 = 0.068 µM) and AC3 (IC50 = 0.083 µM). Substituent -F in ring A (AC4) increased the MAO-B inhibition, followed by -H (AC1), -Br (AC3), and -Cl (AC2). The selectivity index (SI) value of AC4 was high (SI = 82.00) as well as other compounds (44.41 to 98.15). AC4 was found to be a reversible inhibitor as confirmed through analysis using the dialysis method. Interestingly, AC4 was observed to be a noncompetitive MAO-B inhibitor with a rare case and with Ki values of 0.011 ± 0.0036 µM. These experiments confirmed that AC4 is a reversible and potent selective inhibitor of MAO-B. Molecular docking experiments revealed that AC4 showed the highest inhibitory activity with a docking score (-9.510 kcal/mol). A study using molecular dynamics modeling revealed that the protein–ligand complex was more stable. It was observed that AC4 was non-cytotoxic in the study using L929 cell line. In conclusion, compound AC4 shows promise as a MAO-B inhibitor.

Safinamide effect on sleep architecture of motor fluctuating Parkinson's disease patients: A polysomnographic rasagiline-controlled study

IntroductionSleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described. MethodsThis prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1). ResultsSafinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0. ConclusionThis study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission.

Impulse control disorders in Parkinson’s disease: a national Swedish registry study on high-risk treatments and vulnerable patient groups

BackgroundImpulse control disorders (ICDs) are known psychiatric conditions in Parkinson’s disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be...

Identification of Sarmentosin as a Key Bioactive from Blackcurrants (Ribes nigrum) for Inhibiting Platelet Monoamine Oxidase in Humans.

Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro, and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo. These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

Concomitant Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis or Relapsing Multiple Sclerosis.

Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK. Data for ozanimod 0.92mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search ("serotonin syndrome," "neuroleptic malignant syndrome," and "malignant hyperthermia") and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred. No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies. No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs. NCT01647516, NCT02531126, NCT02435992, NCT02576717.

An overview of the role of monoamine oxidase-B in Parkinson’s disease: implications for neurodegeneration and therapy

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both non-motor and motor symptoms, due to the loss of dopamine-producing neurons in the brain. Monoamine oxidase-B (MAO-B) inhibitors are essential in the treatment of PD, as they increase dopamine levels and could potentially slow down the progression of the disease. MAO-B inhibitors block the ability of the enzyme to degrade dopamine in the brain. MAO-B inhibitors work by inhibiting this enzyme, which raises dopamine levels and helps reduce motor symptoms, such as akinesia and stiffness in the muscles. In addition to their impact on dopamine levels, MAO-B inhibitors may possess neuroprotective properties. Research indicates that these inhibitors can shield neurons from the harmful byproducts of dopamine breakdown, such as dihydroxy acetaldehyde and hydrogen peroxide. This neuroprotective effect could potentially slow the progression of PD and protect against neuronal damage. MAO-B inhibitors are effective in treating both advanced and early stages of PD. They are recommended as initial treatments for individuals with early PD and can also be used as supplementary therapy in advanced PD to assist in managing motor complications. Additionally, MAO-B inhibitors have shown promise for the treatment of non-motor symptoms of PD, such as fatigue and sleep disturbances. MAO-B inhibitors are an important class of drugs for the treatment of PD, offering both symptomatic relief and potential disease-modifying effects. The goal of ongoing research and development of MAO-B inhibitors is to enhance their safety and selectivity profiles, which could lead to improved treatment approaches for PD and other neurodegenerative disorders.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease

Depression in Parkinson disease (PD) is common, is disabling and responds poorly to standard antidepressants. Motivational symptoms of depression are particularly prevalent in PD and emerge with loss of dopaminergic innervation of the striatum. Optimizing dopaminergic treatment for PD can improve depressive symptoms. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. Using data from a large (n = 412) longitudinal study of patients with newly diagnosed PD followed over 5 years, we investigated whether there are dissociable effects of dopaminergic medications on different depression symptom dimensions in PD. Previously validated ‘motivation’ and ‘depression’ dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter imaging. We identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists were shown to be effective for treatment of motivational symptoms of depression. In contrast, monoamine oxidase-B inhibitors improved both depressive and motivation symptoms, albeit the latter effect is attenuated in patients with more severe striatal dopaminergic neurodegeneration.

Screening of monoamine oxidase B inhibitors in Tibetan strawberry by ligand fishing based on enzyme functionalized cellulose filter paper

Tibetan strawberry (Fragaria nubicola) is a wild medicinal and edible plant in Tibet possessing various health benefits such as neuroprotection and anti-oxidation. However, there has been little study reported on its chemical constituents. To investigate the inhibitors of monoamine oxidase B (MAO-B) in Tibetan strawberry, we immobilized the enzyme onto cellulose filter paper for the first time to develop a new screening method. Two known glycosides (compounds 1 and 2) and one new iridoid glucoside (Compound 3) were fished out by this method, which was found to effectively inhibit MAO-B with IC50 values of 16.95 ± 0.93, 24.69 ± 0.20, and 46.77 ± 0.78 μM, respectively. Molecular docking and kinetic analysis were performed to reveal the inhibition mechanism of these compounds. Furthermore, compound 1 exhibited neuroprotective effects against 6-OHDA-induced injury on PC12 cells. The developed method exhibits the advantages of rapidness and effectiveness in screening of MAO-B inhibitors from complex herbal extracts.

Baicalin and baicalein from Scutellaria baicalensis Georgi alleviate aberrant neuronal suppression mediated by GABA from reactive astrocytes.

γ-aminobutyric acid (GABA) from reactive astrocytes is critical for the dysregulation of neuronal activity in various neuroinflammatory conditions. While Scutellaria baicalensis Georgi (S. baicalensis) is known for its efficacy in addressing neurological symptoms, its potential to reduce GABA synthesis in reactive astrocytes and the associated neuronal suppression remains unclear. This study focuses on the inhibitory action of monoamine oxidase B (MAO-B), the key enzyme for astrocytic GABA synthesis. Using a lipopolysaccharide (LPS)-induced neuroinflammation mouse model, we conducted immunohistochemistry to assess the effect of S. baicalensis on astrocyte reactivity and its GABA synthesis. High-performance liquid chromatography was performed to reveal the major compounds of S. baicalensis, the effects of which on MAO-B inhibition, astrocyte reactivity, and tonic inhibition in hippocampal neurons were validated by MAO-B activity assay, qRT-PCR, and whole-cell patch-clamp. The ethanolic extract of S. baicalensis ameliorated astrocyte reactivity and reduced excessive astrocytic GABA content in the CA1 hippocampus. Baicalin and baicalein exhibited significant MAO-B inhibition potential. These two compounds downregulate the mRNA levels of genes associated with reactive astrogliosis or astrocytic GABA synthesis. Additionally, LPS-induced aberrant tonic inhibition was reversed by both S. baicalensis extract and its key compounds. In summary, baicalin and baicalein isolated from S. baicalensis reduce astrocyte reactivity and alleviate aberrant tonic inhibition of hippocampal neurons during neuroinflammation.

Effect of particle size versus surface charge on the brain targeting behavior of elastic nanovesicles: In-vitro characterization, comparison between I-optimal and D-optimal statistical optimization and in-vivo pharmacokinetic evaluation

Rasagiline mesylate (RM) is a potent monoamine oxidase-B inhibitor that suffers from extensive hepatic metabolism, low bioavailability, and low brain distribution. Thus, this study aimed to formulate an intranasal nanovesicular system with high RM encapsulation (EE%) and enhanced delivery to the brain tissues. In this perspective, negatively and positively charged RM-transfersomal vesicles were prepared, characterized and the formulation parameters were statistically optimized as per two different response surface methodologies namely, I-optimal and D-optimal design. Although both statistical designs acted almost similarly in terms of experimental response analysis; the I-optimal design might be functioning better in terms of formulations’ optimization and response prediction with higher desirability factors. Consequently, the optimized negative transfersomes (particle size: 213 nm, EE%:62.55 %) and positive transfersomes (particle size: 515 nm, EE%:70.9 %) suggested by the I-optimal design were furtherly formulated, characterized for their in-vitro release, elasticity, transmission electron microscope and pH. Finally, both systems were administered intranasally and compared to an intravenous RM solution where the optimized positive transfersomes has shown significantly higher brain targeting efficiency, positive direct transfer percentage values and longer brain mean residence time. These results suggested that the surface charge of the formulated vesicles could be more effective factor -than the particle size-in enhancing the brain bioavailability of the administered drugs.

Iron-catalysed C–H ortho-arylation of edaravone, a promising monoamine oxidase-B inhibitor

Edaravone is a neuroactive drug that is currently used in the treatment of stroke patients and shows promise against a range of neurodegenerative processes including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. We show that iron-catalysed C–H functionalisation of edaravone and its derivatives can be exploited to generate a small library of 21 arylated edaravones, while the results of a preliminary computational binding study of these derivatives predicts that they should all bind more strongly in the active site of monoamine oxidase-B than edaravone.

A decision support system based on recurrent neural networks to predict medication dosage for patients with Parkinson's disease

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.

CGRP causes anxiety via HP1γ–KLF11–MAOB pathway and dopamine in the dorsal hippocampus

Calcitonin gene-related peptide (CGRP) is a neuropeptide that causes anxiety behavior; however, the underlying mechanisms remain unclear. We found that CGRP modulates anxiety behavior by epigenetically regulating the HP1γ-KLF-11-MAOB pathway and depleting dopamine in the dorsal hippocampus. Intracerebroventricular administration of CGRP (0.5 nmol) elicited anxiety-like behaviors in open field, hole-board, and plus-maze tests. Additionally, we observed an increase in monoamine oxidase B (MAOB) levels and a concurrent decrease in dopamine levels in the dorsal hippocampus of mice following CGRP administration. Moreover, CGRP increased abundance the transcriptional regulator of MAOB, Krüppel-like factor 11 (KLF11), and increased levels of phosphorylated heterochromatin protein (p-HP1γ), which is involved in gene silencing, by methylating histone H3 in the dorsal hippocampus. Chromatin immunoprecipitation assay showed that HP1γ was recruited to the Klf11 enhancer by CGRP. Furthermore, infusion of CGRP (1 nmol) into the dorsal hippocampus significantly increased MAOB expression as well as anxiety-like behaviors, which were suppressed by the pharmacological inhibition or knockdown of MAOB. Together, these findings suggest that CGRP reduces dopamine levels and induces anxiety-like behavior through epigenetic regulation in the dorsal hippocampus.

Probing the inhibition of MAO-B by chalcones: an integrated approach combining molecular docking, ADME analysis, MD simulation, and MM-PBSA calculations.

Monoamine oxidase B (MAO-B), an enzyme of significant relevance in the realm of neurodegenerative disorders, has garnered considerable attention as a potential target for therapeutic intervention. Natural compounds known as chalcones have shown potential as MAO-B inhibitors. In this particular study, we employed a multimodal computational method to evaluate the inhibitory effects of chalcones on MAO-B. Molecular docking methods were used to study and assess the complicated binding interactions that occur between chalcones and MAO-B. This extensive analysis provided a valuable and deep understanding of possible binding methods as well as the key residues implicated in the inhibition process. Furthermore, the ADME investigation gave valuable insights into the pharmacokinetic properties of chalcones. This allowed them to be assessed in terms of drug-like attributes. The use of MD simulations has benefited in the research of ligand-protein interactions' dynamic behaviour and temporal stability. MM-PBSA calculations were also done to estimate the binding free energies and acquire a better knowledge and understanding of the binding affinity between chalcones and MAO-B. Our thorough method gives a thorough knowledge of chalcones' potential as MAO-B inhibitors, which will be useful for future experimental validation and drug development efforts in the context of neurodegenerative illnesses.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction.

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer's disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1-90.0 nM) and MAO-B (IC50 in the range of 6.7-32.6 nM). Computational studies were conducted to elucidate the structure-activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.