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Fulltext Emodin Derivatives as Multi-Target-Directed Ligands Inhibiting Monoamine Oxidase and Antagonizing Vasopressin V1A Receptors

Paudel P, Shrestha S, Park SE, Seong SH, Fauzi FM, Jung HA, et al.

ACS Omega, 2020 Oct 20;5(41):26720-26731.
PMID: 33110998 DOI: 10.1021/acsomega.0c03649

The brain neurotransmitter level is associated with the pathology of various neurodegenerative diseases, and age-dependent increase in the blood level of vasopressin, human brain monoamine oxidase (hMAO) level, oxidative stress, and imbalance in aminergic signaling are common disease-modifying factors leading to various neurodegenerative disorders. Based on the reports of emodin in hMAO inhibition and antagonist effect on the vasopressin V1A receptor, in this study we synthesized six emodin derivatives and evaluated their effects on MAO activity and G protein-coupled receptors. Among them, 4-hydroxyemodin and 5-hydroxyemodin were potent inhibitors of hMAO, and 2-hydroxyemodin and 5-hydroxyemodin were good V1AR antagonists. In silico molecular docking simulation revealed that the hydroxyl group at C2, C4, and C5 of the respective compounds interacted with prime residues, which corroborates the in vitro effect. Likewise, these three derivatives were predicted to have good drug-like properties. Overall, our study demonstrates that the hydroxyl derivatives of emodin are multi-target-directed ligands that may act as leads for the design and development of a therapy for central nervous system disorders.
Fulltext Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists

Paudel P, Park SE, Seong SH, Fauzi FM, Jung HA, Choi JS

J Integr Neurosci, 2023 Jan 05;22(1):10.
PMID: 36722239 DOI: 10.31083/j.jin2201010

BACKGROUND: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy.
METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.
RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.
CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.
Fulltext Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I

Prajapati R, Park SE, Seong SH, Paudel P, Fauzi FM, Jung HA, et al.

Biomolecules, 2021 Jul 08;11(7).
PMID: 34356625 DOI: 10.3390/biom11071001

Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson's disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.
Applicability assessment of empty fruit bunches from palm oil mills for use as bio-solid refuse fuels

Yoo HM, Park SW, Seo YC, Kim KH

J Environ Manage, 2019 Mar 15;234:1-7.
PMID: 30599325 DOI: 10.1016/j.jenvman.2018.11.035

Palm kernel shells (PKS), empty fruit bunches (EFB), and trunks are by-products of the palm oil industry and form approximately 50 wt % of fresh fruit bunch (FFB). In particular, EFB accounts for approximately 20 wt % of FFB. Although large amounts of EFB are generated from palm oil mills every year in Indonesia and Malaysia, EFB is treated as waste because commercial technologies for thermo-chemical conversion of EFB into renewable energy are still under development. A robust conversion method can transform EFB into an appealing renewable energy source. In order to secure this renewable energy source, Korea can import EFB as biomass. This paper investigates literature on the status of utilization of EFB, by-products from palm oil mills in order to identify the best available technological process to use EFB as bio-solid refuse fuels (SRF). Meanwhile, physico-chemical analyses (proximate, elemental, and calorific value analyses), biomass and heavy metal content were measured in order to assess whether EFB would be suitable for use as a bio-SRF, in accordance with the Korean quality standard for SRF. According to the analysis results, EFB showed applicability to use as bio-SRF; main analysis results - moisture (9.63 wt %), ash (5.94 wt %), biomass content (97.82 wt %) and calorific value (3668 kcal kg).
Luteolin, a Potent Human Monoamine Oxidase-A Inhibitor and Dopamine D4 and Vasopressin V1A Receptor Antagonist

Park SE, Paudel P, Wagle A, Seong SH, Kim HR, Fauzi FM, et al.

J Agric Food Chem, 2020 Sep 30;68(39):10719-10729.
PMID: 32869630 DOI: 10.1021/acs.jafc.0c04502

Luteolin, a flavonoid widely distributed in the plant kingdom, contains two benzene rings and hydroxyl groups, and this structural specificity contributes to its diverse biological activities. However, no previous studies have simultaneously investigated the therapeutic potency of luteolin isolated from a plant as an antipsychotic and antidepressant. Here, luteolin exhibited selective inhibition of hMAO-A (IC50 = 8.57 ± 0.47 μM) over hMAO-B (IC50 > 100 μM). In silico proteochemometric modeling predicted promising targets of luteolin, and verification via cell-based G protein-coupled receptor functional assays showed that luteolin is a selective antagonist of the vasopressin receptor V1AR (IC50 = 19.49 ± 6.32 μM) and the dopamine D4 receptor (IC50 = 39.59 ± 1.46 μM). Molecular docking showed the tight binding of luteolin with a low binding score and the high stability of the luteolin-receptor complex, corroborating its functional effect. Thus, hMAO-A, hD4R, and hV1AR are prime targets of luteolin and potential alternatives for the management of neurodegenerative diseases.