Monoamine Oxidase B is considered a successful target for developing antiparkinsonian drugs. Due to the side effects of current MAO-B inhibitors, there’s an urgent need for novel potent and highly selective MAO-B inhibitors. A recent study has shown that coumarins tend to be more selective towards MAO-B than MAO-A when connected to a hex-5-ynyloxy chain at position 6 in contrast to their C7-isomers. The present study describes the mode of interaction of the C6 and C7-substituted coumarin isomers characterized by their difference in selectivity towards MAO-B through molecular docking and molecular dynamics simulations in an effort to elucidate the structural components and molecular interactions that may be responsible for MAO-B selectivity. Three isomeric coumarin pairs connected to ether chain at position 6 or 7 were taken from the literature and modelled according to their IUPAC nomenclature. Molecular docking study revealed one π- π stacking interaction with Tyr-326 in common between the selective coumarin C6-isomers. Resulting complexes of one isomeric coumarin pair that displayed the highest selectivity shift towards MAO-B were subject to 100 ns molecular dynamics simulations study to analyze the stability of the docked complexes. Molecular dynamics revealed that the C7-isomer is relatively stable in both MAO isoforms through the simulation duration, whereas the C6-isomer deemed unstable for MAO-A which may be due to the bulky Phe-208 residue in MAO-A. Our results might be applied for further development and optimization of coumarin derivatives into a successful drug against Parkinson’s disease. Communicated by Ramaswamy H. Sarma

Parkinson’s disease is considered the second most frequent neurodegenerative disease. It is described by the loss of dopaminergic neurons in the mid-brain. For many decades, L-DOPA has been considered as the gold standard for treating Parkinson’s disease motor symptoms, however, due to the decrease of efficacy, in the long run, there is an urgent need for novel antiparkinsonian drugs. Caffeine derivatives have been reported several times for their neuroprotective properties and dual blockade of monoamine oxidase (MAO) and adenosine A_2A receptors (AA_2AR). Natural products are currently attracting more focus due to structural diversity and safety in contrast to synthetic drugs. In the present work, computational studies were conducted on natural product-like caffeine derivatives to search for novel potent candidates acting as dual MAO-B inhibitors/AA_2AR antagonists for Parkinson’s disease. Our findings revealed two natural products among the top hits: CNP0202316 and CNP0365210 fulfill the requirements of drugs acting on the brain. The selected lead compounds were further studied using molecular dynamics simulation to assess their stability with MAO-B. Current findings might shift the interest towards natural-based compounds and could be exploited to further optimize caffeine derivatives into a successful dual-target-directed drug for managing and halting the neuronal damage in Parkinson’s disease patients.

Coumarins are a highly privileged scaffold in medicinal chemistry. It is present in many natural products and is reported to display various pharmacological properties. A large plethora of compounds based on the coumarin ring system have been synthesized and were found to possess biological activities such as anticonvulsant, antiviral, anti-inflammatory, antibacterial, antioxidant as well as neuroprotective properties. Despite the wide activity spectrum of coumarins, its naturally occurring derivatives are yet to be investigated in detail. In the current study, a chemical library was created to assemble all chemical information related to naturally occurring coumarins from the literature. Additionally, a multi-stage virtual screening combining QSAR modeling, molecular docking, and ADMET prediction was conducted against monoamine oxidase B and acetylcholinesterase, two relevant targets known for their neuroprotective properties and 'disease-modifying' potential in Parkinson's and Alzheimer's disease. Our findings revealed ten coumarin derivatives that may act as dual-target drugs against MAO-B and AChE. Two coumarin candidates were selected from the molecular docking study: CDB0738 and CDB0046 displayed favorable interactions for both proteins as well as suitable ADMET profiles. The stability of the selected coumarins was assessed through 100 ns molecular dynamics simulations which revealed promising stability through key molecular interactions for CDB0738 to act as dual inhibitor of MAO-B and AChE. However, experimental studies are necessary to evaluate the bioactivity of the proposed candidate. The current results may generate an increasing interest in bioprospecting naturally occurring coumarins as potential candidates against relevant macromolecular targets by encouraging virtual screening studies against our chemical library.Communicated by Ramaswamy H. Sarma.

The Polyphenol oxidase (PPO) leads to the enzymatic browning of fruits and vegetables and needs to be prevented in food browning and quality. The present study aimed to investigate the use of natural extracts and chemical inhibitors to prevent browning of the PPO of blackberries. Purification, characterization, and kinetics of PPO of blackberry parameters for five substrates, namely, pyrocatechol, 4-methylcatechol, Pyrogallol, Gallic acid, and tyrosine, were described. The results showed that the DEAE-Sepharose and Superdex G-200 purification methods, which achieved electrophoretic purity, increased PPO activity by 556 fold. Purification with Sephadex GE-200 and SDS-PAGE reveals two PPO isoenzymes with an apparent molecular weight of 22 kD and 70 kD. The optimum pH and temperature values indicated were 6.6 and 25°C, respectively. The PPO showed variable affinity towards o-dihydroxy phenolic substrates with catecholase activity but without any activity observed with phenol, a monohydroxy substrate, and it was very effective towards pyrocatechol, pyrogallol, and 4-methyl catechol. The results revealed that inhibition of the PPO using both synthetic inhibitors and natural extracts was the most effective method. Quercetin and ascorbic acid showed higher inhibition with the lowest Ki values. Fresh onion (Allium cepa) and wild Arbutus unedo extract were able to inhibit the blackberry PPO activity up to 50% and 60%, respectively. Therefore, the use of natural extracts from Arbutus unedo L as anti-browning agents on the blackberry PPO may provide new insight to overcome the enzymatic browning.

Longitudinal magnetization curves and giant magnetoimpedance (GMI) analyses are combined to investigate the anisotropy and magnetization processes of dc-current-self-annealed ${\mathrm{Co}}_{\mathrm{68.15}}{\mathrm{Fe}}_{\mathrm{4.35}}{\mathrm{Se}}_{\mathrm{12.5}}{\mathrm{B}}_{\mathrm{15}}$ wires. The magnetization curves show an almost anhysteretic behavior with small Barkhausen jumps occurring at a critical field $H^{*}$ . This unusual shape is in very good agreement with the high resolution GMI response to the field, which reflects the circumferential bias permeability. Magnetization curves yield information on the bulk properties, while GMI allows the investigation of the surface region of the sample. The anisotropy constant is calculated using initial-magnetization curves and the resonance condition, yielding interesting conclusions concerning the inhomogeneity of the wires.

Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain. Current treatments provide limited symptomatic relief without halting disease progression. A multi-targeting approach has shown potential benefits in treating neurodegenerative diseases. In this study, we employed in silico approaches to explore the COCONUT natural products database and identify novel drug candidates with multi-target potential against relevant Parkinson's disease targets. QSAR models were developed to screen for potential bioactive molecules, followed by a hybrid virtual screening approach involving pharmacophore modeling and molecular docking against MAO-B, AA_2AR, and NMDAR. ADME evaluation was performed to assess drug-like properties. Our findings revealed 22 candidates that exhibited the desired pharmacophoric features. Particularly, two compounds: CNP0121426 and CNP0242698 exhibited remarkable binding affinities, with energies lower than -10 kcal/mol and promising interaction profiles with the chosen targets. Furthermore, all the ligands displayed desirable pharmacokinetic properties for brain-targeted drugs. Lastly, molecular dynamics simulations were conducted on the lead candidates, belonging to the dihydrochalcone and curcuminoid class, to evaluate their stability over a 100 ns timeframe and compare their dynamics with reference complexes. Our findings revealed the curcuminoid CNP0242698 to have an overall better stability with the three targets compared to the dihydrochalcone, despite the high ligand RMSD, the curcuminoid CNP0242698 showed better protein stability, implying ligand exploration of different orientations. Similarly, AA_2AR exhibited higher stability with CNP0242698 compared to the reference complex, despite the high initial ligand RMSD due to the bulkier active site. In NMDAR, CNP0242698 displayed good stability and less fluctuations implying a more restricted conformation within the smaller active site of NMDAR. These results may serve as lead compounds for the development and optimization of natural products as multi-target disease-modifying natural remedies for Parkinson's disease patients. However, experimental assays remain necessary to validate these findings.Communicated by Ramaswamy H. Sarma.