• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.155-159
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• 2018

For regulatory approval of a new drug, the most preferred and reliable source of evidence would be randomized controlled trials (RCT). However, a great number of drugs, being developed as well as already marketed and being used, usually lack proper indications for children. It is imperative to develop properly evaluated drugs for children. And expanding the use of already approved drugs for other indications will benefit patients and the society. Nevertheless, to get an approval for expansion of indications, most often with off-label experiences, for drugs that have been approved or for the development of pediatric indications, either during or after completing the main drug development, conducting RCTs may not be the only, if not right, way to take. Extrapolation strategies and modelling & simulation for pediatric drug development are paving the road to the better approval scheme. Making the use of data sources other than RCT such as EHR and claims data in ways that improve the efficiency and validity of the results (e.g., randomized pragmatic trial and randomized registry trial) has been the topic of great interest all around the world. Regulatory authorities should adopt new methodologies for regulatory approval processes to adapt to the changes brought by increasing availability of big and real world data utilizing new tools of technological advancement.

• Bulletin of the Korean Chemical Society
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• v.34 no.4
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• pp.1212-1220
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• 2013

The human coagulation factor XI (FXI) is a serine protease that plays a significant role in blocking of the blood coagulation cascade as an attractive antithrombotic target. Selective inhibition of FXIa (an activated form of factor XI) disrupts the intrinsic coagulation pathway without affecting the extrinsic pathway or other coagulation factors such as FXa, FIIa, FVIIa. Furthermore, targeting the FXIa might significantly reduce the bleeding side effects and improve the safety index. This paper reports on a docking-based three dimensional quantitative structure activity relationship (3D-QSAR) study of the potent FXIa inhibitors, the chloro-phenyl tetrazole scaffold series, using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Due to the characterization of FXIa binding site, we classified the alignment of the known FXIa inhibitors into two groups according to the docked pose: S1-S2-S4 and S1-S1'-S2'. Consequently, highly predictive 3D-QSAR models of our result will provide insight for designing new potent FXIa inhibitors.

• YAKHAK HOEJI
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• v.52 no.2
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• pp.151-159
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• 2008

Consultation program for pharmaceutical development is a new system in which pharmaceutical companies meet and discuss scientific and/or regulatory issues with drug regulatory authority in the research process and before submitting new drug applications. This program helps pharmaceutical companies reduce uncertainties in the research and development and increase the possibilities of getting drug marketing approval. Developed countries such as US, EU, and Japan have implemented various forms of pre-submission meetings or consultation programs since the mid-1990s. The rapid development of technology in pharmaceutical R&D increases the importance of communication between drug development companies and drug regulatory authority in Korea, too. In designing the consultation program, it is desirable to focus on the stages of clinical trials which take the longest period of time and the biggest amount of money in the pharmaceutical R&D process. We suggested that results or recommendations by drug regulatory authorities in pre-submission meetings or consultations be formally documented and considered in review process. Explicit scientific reasons are required for changing the results from consultations.

• YAKHAK HOEJI
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• v.52 no.5
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• pp.331-344
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• 2008

Recently, the FDA (Food and Drug Administration) of the United States and many advanced countries remark biomarkers and surrogate endpoints as a critical path tool on model based drug development. Economic, technical and social profit on model based drug development like a reduction of the length of research and development have been achieved. Therefore we summarize previous studies about biomarkers and surrogate endpoints and suggest a development direction of therapeutic agents. In diabetes mellitus (DM) and osteoporosis, there are remarkable increases in number of patients and most of patients take medicine during their whole lifetime. For this reason, many patients with DM and osteoporosis have a tolerance on their medicine. We expect that research and development on biomarkers and surrogate endpoints will contribute to new drug development on DM and osteoporosis. Biomarkers for DM are blood levels of glucose, insulin, ${HbA}_{1c}$, CRP, alpha-glucosidase, adiponectin and DPP-4. Among these, validated surrogate endpoints for DM are blood levels of glucose, insulin and ${HbA}_{1c}$ Biomarkers for osteoporosis are BMD, BMC, trabecular volume, ICTP, DPD, osteocalcin, the activity of osteoclast and production of osteoblast. The validated surrogate endpoints for osteoporosis are BMD only. This review summarizes all suggested biomarkers and surrogate endpoints in DM and osteoporosis. The biomarkers are classified by drugs, and the method of validation for surrogate endpoints is suggested. This information would contribute to suggest a direction of DM and osteoporosis therapeutic agent development.

• Archives of Pharmacal Research
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• v.25 no.3
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• pp.229-239
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• 2002

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.

• Journal of Pharmacopuncture
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• v.19 no.1
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• pp.7-15
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• 2016

Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the 'apicoplast', which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle's function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug resistance.

• Korean Journal of Microbiology
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• v.54 no.2
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• pp.140-145
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• 2018

The most energy-intensive processes in lipids extraction were the disruption of the cell wall of microalgae. Here, we tried to extract lipids through lysis using virus-infecting microalgae, to compare with those by the other two methods using microwave or ultrasonication. The lipids yield using viral infection was not significantly different from those using ultrasonication and microwave oven. This suggests that the same amount of lipids can be obtained with low energy and costs, as well as that microalgal lipids extraction by chlorella virus infection might provide the price competitiveness in biodiesel production even if it will be applied to mass production facilities.

• Journal of Microbiology and Biotechnology
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• v.16 no.6
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• pp.933-938
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• 2006

Decaprenyl diphosphate synthase (DPS) is the key enzyme for the production of coenzyme $Q_{10}$ ($CoQ_{10}$). A dps gene from Sinorhizobium meliioti KCCM 11232 (IFO 14782) was isolated by PCR and then cloned in Escherichia coli. DNA sequencing analysis revealed an open reading frame of 1,017 bp encoding a 338-amino-acid protein. The protein was identical at the 98% level to the putative octaprenyl diphosphate synthase (IspB) of S. meliloti 1021. The deduced amino acid sequence included the DDxxD domains conserved in the majority of the prenyl diphosphate synthases. Heterologous expression in E. coli BL21 (DE3) was carried out, and the $CoQ_{10}$ produced was then analyzed by HPLC. E. coli BL21 (DE3) harboring the dps gene from S. melioti produced CoQ$_{10}$ in addition to endogenous coenzyme Q$_8$ (CoQ$_8$), whereas wild-type E. coli BL21 (DE3) host did not have the ability of producing CoQ$_{10}$. The results suggest that the putative dps from S. meliloti KCTC 2353 encoded the DPS.

• Genomics & Informatics
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• v.17 no.3
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• pp.28.1-28.9
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• 2019

Bar-code (tag) microarrays of yeast gene-deletion collections facilitate the systematic identification of genes required for growth in any condition of interest. Anti-sense strands of amplified bar-codes hybridize with ~10,000 (5,000 each for up-and down-tags) different kinds of sense-strand probes on an array. In this study, we optimized the hybridization processes of an array for fission yeast. Compared to the first version of the array (11 ㎛, 100K) consisting of three sectors with probe pairs (perfect match and mismatch), the second version (11 ㎛, 48K) could represent ~10,000 up-/ down-tags in quadruplicate along with 1,508 negative controls in quadruplicate and a single set of 1,000 unique negative controls at random dispersed positions without mismatch pairs. For PCR, the optimal annealing temperature (maximizing yield and minimizing extra bands) was 58℃ for both tags. Intriguingly, up-tags required 3× higher amounts of blocking oligonucleotides than down-tags. A 1:1 mix ratio between up- and down-tags was satisfactory. A lower temperature (25℃) was optimal for cultivation instead of a normal temperature (30℃) because of extra temperature-sensitive mutants in a subset of the deletion library. Activation of frozen pooled cells for >1 day showed better resolution of intensity than no activation. A tag intensity analysis showed that tag(s) of 4,316 of the 4,526 strains tested were represented at least once; 3,706 strains were represented by both tags, 4,072 strains by up-tags only, and 3,950 strains by down-tags only. The results indicate that this microarray will be a powerful analytical platform for elucidating currently unknown gene functions.

• Bulletin of the Korean Chemical Society
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• v.31 no.10
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• pp.2761-2770
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• 2010

In this study, we have developed QSAR models for a series of 38 piperidine-4-carboxamide CCR5 antagonists using CoMFA, CoMSIA and HQSAR methods. Developed models showed good statistics in terms of $q^2$ and $r^2$ values. Best predictions obtained with standard CoMFA model ($r^2$ = 0.888, $q^2$ = 0.651) and combined CoMSIA model ($r^2$ = 0.892, $q^2$ = 0.665) with electrostatics and H-bond acceptor parameter. The validity of developed models was assessed by test set of 9 compounds, which showed good predictive correlation coefficient for CoMFA (0.804) and CoMSIA (0.844). Bootstrapped analysis showed statistically significant and robust CoMFA (0.968) and CoMSIA (0.936) models. Best HQSAR model was obtained with a $q^2$ of 0.662 and $r^2$ of 0.936 using atom, connection, hydrogen, donor and acceptor as parameters and fragment size (7-10) with optimum number of 6 components. Predictive power of developed HQSAR model was proved by test set and it was found to be 0.728.