• Journal of Korean Neurosurgical Society
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• v.58 no.1
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• pp.1-8
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• 2015

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3817-3825
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• 2015

Background: The human protein methyl-transferase DOT1L catalyzes the methylation of histone H3 on lysine 79 (H3K79) at homeobox genes and is also involved in a number of significant processes ranging from gene expression to DNA-damage response and cell cycle progression. Inhibition of DOT1L activity by shRNA or small-molecule inhibitors has been established to prevent proliferation of various MLL-rearranged leukemia cells in vitro, establishing DOT1L an attractive therapeutic target for mixed lineage leukemia (MLL). Most of the drugs currently in use for the MLL treatment are reported to have low efficacy, hence this study focused on various natural compounds which exhibit minimal toxic effects and high efficacy for the target receptor. Materials and Methods: Structures of human protein methyl-transferase DOT1L and natural compound databases were downloaded from various sources. Virtual screening, molecular docking, dynamics simulation and drug likeness studies were performed for those natural compounds to evaluate and analyze their anti-cancer activity. Results: The top five screened compounds possessing good binding affinity were identified as potential high affinity inhibitors against DOT1L's active site. The top ranking molecule amongst the screened ligands had a Glide g-score of -10.940 kcal/mol and Glide e-model score of -86.011 with 5 hydrogen bonds and 12 hydrophobic contacts. This ligand's behaviour also showed consistency during the simulation of protein-ligand complex for 20000 ps, which is indicative of its stability in the receptor pocket. Conclusions: The ligand obtained out of this screening study can be considered as a potential inhibitor for DOT1L and further can be treated as a lead for the drug designing pipeline.

• Bulletin of the Korean Chemical Society
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• v.30 no.9
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• pp.2083-2086
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• 2009

Human vascular endothelial growth factor receptor 2 (hVEGFR2) is an important signaling protein involved in angiogenesis and attractive drug target in cancer therapy. It has been reported that flavonols, a class of flavonoids, have anti-angiogenic activity in various cancer cell lines. We performed receptor-oriented pharmacophore based in silico screening for identification of hVEGFR2 inhibitors from flavonol database. By comparing with three X-ray complex structures of hVEGFR2 and its inhibitors, we evaluated the specific interactions between inhibitors and receptors and determined a single pharmacophore map. This map consisted of four features, a hydrogen bonding acceptor (HBA) on Cys917, two hydrogen bonding donors on Glu917 (HBD1) and Glu883 (HBD2), and one hydrophobic interaction (Lipo) with Val846, Ala864, Val897, Val914 and Phe1045 of hVEGFR2. Using this map, we searched a flavonol database including 9 typical flavonols and proposed that five flavonols, kaempferol, quercetin, fisetin, morin, and rhamnetin can be potent inhibitors of hVEGFR2. 3-OH of C-ring and 4’-OH of B-ring of flavonols are the essential features for hVEGFR2 inhibition. This study will be helpful for understanding the mechanism of inhibition of hVEGFR2 by natural products.

• Biomolecules & Therapeutics
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• v.31 no.3
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• pp.241-252
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• 2023

The era of innovative RNA therapies using antisense oligonucleotides (ASOs), siRNAs, and mRNAs is beginning. Since the emergence of the concept of ASOs in 1978, it took more than 20 years before they were developed into drugs for commercial use. Nine ASO drugs have been approved to date. However, they target only rare genetic diseases, and the number of chemistries and mechanisms of action of ASOs are limited. Nevertheless, ASOs are accepted as a powerful modality for next-generation medicines as they can theoretically target all disease-related RNAs, including (undruggable) protein-coding RNAs and non-coding RNAs. In addition, ASOs can not only downregulate but also upregulate gene expression through diverse mechanisms of action. This review summarizes the achievements in medicinal chemistry that enabled the translation of the ASO concept into real drugs, the molecular mechanisms of action of ASOs, the structure-activity relationship of ASO-protein binding, and the pharmacology, pharmacokinetics, and toxicology of ASOs. In addition, it discusses recent advances in medicinal chemistry in improving the therapeutic potential of ASOs by reducing their toxicity and enhancing their cellular uptake.

• Journal of Pharmacopuncture
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• v.18 no.3
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• pp.11-18
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• 2015

Objectives: Systems biology is a novel subject in the field of life science that aims at a systems' level understanding of biological systems. Because of the significant progress in high-throughput technologies and molecular biology, systems biology occupies an important place in research during the post-genome era. Methods: The characteristics of systems biology and its applicability to traditional medicine research have been discussed from three points of view: data and databases, network analysis and inference, and modeling and systems prediction. Results: The existing databases are mostly associated with medicinal herbs and their activities, but new databases reflecting clinical situations and platforms to extract, visualize and analyze data easily need to be constructed. Network pharmacology is a key element of systems biology, so addressing the multi-component, multi-target aspect of pharmacology is important. Studies of network pharmacology highlight the drug target network and network target. Mathematical modeling and simulation are just in their infancy, but mathematical modeling of dynamic biological processes is a central aspect of systems biology. Computational simulations allow structured systems and their functional properties to be understood and the effects of herbal medicines in clinical situations to be predicted. Conclusion: Systems biology based on a holistic approach is a pivotal research methodology for understanding the mechanisms of traditional medicine. If systems biology is to be incorporated into traditional medicine, computational technologies and holistic insights need to be integrated.

• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.1-11
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• 2015

Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named $LPA_1-LPA_6$. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.

• BMB Reports
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• v.49 no.11
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• pp.623-628
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• 2016

GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. This study revealed that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. At the molecular level, GPR78 regulated cell motility through the activation of $G{\alpha}q$-RhoA/Rac1 pathway. We further demonstrated that in vivo, the knockdown of GPR78 inhibited lung cancer cell metastasis. These findings suggest that GPR78 is a novel regulator for lung cancer metastasis and may serve as a potential drug target against metastatic human lung cancer.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.5 no.2
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• pp.152-157
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• 2019

Polo-like kinase 1 (Plk1) is crucial regulator of cell cycle progression during mitosis. It is known to highly overexpress in many different tumor types, and has been implicated as a potential antimitotic cancer target. The phosphopeptide, Pro-Leu-His-Ser-p-Thr (PLHSpT), was shown a high level of affinity and specificity for the polo-box domain (PBD) of Plk1. However, the peptide has the limitation of cell permeability. We designed the derivatives to enhance the limitation of PLHSpT using drug delivery system. In addition, we synthesized and evaluated its radiotracer for tumor diagnosis. This review discusses the derivative and radiotracer that are suitable for tumor treatment and diagnosis for PBD of Plk1.

• Bulletin of the Korean Chemical Society
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• v.33 no.1
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• pp.111-114
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• 2012

Androgen receptor (AR) is ligand-inducible nuclear hormone receptor which has been focused on key molecular target in growth and progression of prostate cancer. We synthesized a series of 4-aryl 2-substituted aniline-thiazole analogs and evaluated their anti-cancer activity in AR-dependent human prostate cancer LNCap cells. Among them, the compound 6 inhibited the tumor growth in LNCap-inoculated xenograft model.

• Journal of Integrative Natural Science
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• v.8 no.3
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• pp.209-213
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• 2015

Influenza A virus (H1N1) causes and spreads infectious diseases and becomes a major health threat in humans. Among the subtypes of influenza virus, neuraminidase (NA) plays an important role in viral life cycle and becomes an attractive therapeutic target. Currently two NA inhibitors namely Zanamivir and Oseltamivir are available for treating infectious diseases. Recently five naturally derived polyphenols extracted from Phellinus baumii was reported as inhibitors against NA. Molecular docking is powerful tool in computer aided drug designing which aids in exploring and elucidating the properties of the molecules from their 3D structure. Hence, in the present study, molecular docking was carried out on reported polyphenols isolated from ethanolic extract of fruiting bodies of Phellinus baumii. The objective of this work was to study the interaction and to propose the binding mode of these compounds within the binding site of H1N1 neuraminidase. The results showed these compounds had better binding energy and H-bond interactions with the important active site residues of the receptor which authenticate these compounds contributes to inhibitory activity of neuraminidase to treat influenza infection.