• Journal of the Korean Crystal Growth and Crystal Technology
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• v.26 no.6
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• pp.232-237
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• 2016

Cocrystallization of active pharmaceutical ingredients has been widely recognized as a versatile tool to regulate the physical properties of pharmaceutical compounds through designed crystal structures. Grinding or milling has been especially useful to screen the feasibility of cocrystal formation, and the addition of a small amount of liquid is routinely necessary. In the present study, the effect of temperature was studied for the milling cocrystallization of ibuprofen and nicotinamide to establish a liquid-free method. The milling-induced cocrystallization was more effective with liquid nitrogen cooling than at room temperature, which was confirmed by XRD and DSC analyses. This behavior was attributed to the limited molecular mobility below the glass transition temperatures of the cocrystal components, which made it effective to destruct the crystals of raw materials and consequently form the ibuprofen/nicotinamide cocrystal. Further studies would be necessary to establish the utility of the current conclusion to the field of pharmaceutical crystallization.

• Journal of the Korean Chemical Society
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• v.60 no.1
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• pp.9-15
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• 2016

The theoretical investigation has been performed to predict detonation velocity, detonation pressure, and thermodynamic stability of HMX/LLM-116 cocrystal. All possible geometries of HMX, LLM-116, and cocrystal have been optimized at the B3LYP/cc-pVTZ level of theory. The binding energy for the trigger bond and cluster has been calculated to predict the thermodynamic stability. The MP2 binding energies were obtained using single point energy calculation at the B3LYP optimized geometries, and the density has been calculated from monte carlo integration. The detonation velocity and detonation pressure have been calculated using Kamlet-Jacobs equation, while enthalpy has been predicted at the CBS-Q level of theory.

• Bulletin of the Korean Chemical Society
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• v.34 no.2
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• pp.545-548
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• 2013

It has been shown that calculating atomic charges using quantum mechanical level theory greatly improves the accuracy of docking. A protocol was developed and shown to be effective. That this protocol works is just a manifestation of the fact that electrostatic interactions are important in protein-ligand binding. In order to investigate how the same protocol helps in prediction of binding affinities, we took a series of known cocrystal structures of influenza neuraminidase inhibitors with the receptor and performed docking with Glide SP, Glide XP, and QPLD, the last being a workflow that incorporates QM/MM calculations to replace the fixed atomic charges of force fields with quantum mechanically recalculated ones at a given docking pose, and predicted the binding affinities of each cocrystal. The correlation with experimental binding affinities considerably improved with QPLD compared to Glide SP/XP yielding $r^2$ = 0.83. The results suggest that for binding sites, such as that of neuraminidase, which are laden with hydrophilic residues, protocols such as QPLD which utilizes QM-based atomic charges can better predict the binding affinities.

• Polymer(Korea)
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• v.37 no.5
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• pp.663-668
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• 2013

The effects of polymers on the cocrystallization of adefovir dipivoxil (AD) and suberic acid (SUB) were investigated. The polymeric additives in the present study were poly(ethylene glycol) (PEG) and poly(acrylic acid) (PAA). When the polymers were added to the solution of AD and SUB, their effects were limited to the morphology and crystallinity of the AD/SUB cocrystal, which could be also achieved without polymeric additives by the excess amount of SUB in the solution or through the solvent-assisted grinding. When the polymers were mixed with AD before adding SUB in the solution, PEG was dramatically more effective at the same amount with possible alteration of the cocrystal structure. Also, PAA completely inhibited the formation of crystals. The present study demonstrated that the effects of polymers on the cocrystallization could be tuned by simply modifying the mixing strategy.

• Proceeding of EDISON Challenge
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• 2016.03a
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• pp.126-130
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• 2016

Epidermal growth factor receptor(EGFR)는 HER family에 속하는 tyrosine kinase receptor로서 다양한 하류경로로 신호를 전달하여 세포 증식, 혈관 형성, 세포 사멸을 억제하는 역할을 한다. EGFR이 폐암의 형성에 중요한 역할을 하고 많은 상피세포 종양에서 비정상적으로 활성화됨에 따라 암 치료에 중요한 역할을 하고 있어 EGFR tyrosine kinase inhibitor(TKI)에 관한 많은 연구가 이루어졌다. 위와 같은 약 개발에 있어서 현재 가상 시뮬레이션을 통한 약 후보물질 개발이 진행되고 있다. 특히, Molecular docking 시뮬레이션은 기존의 실험적인 기술(X-ray crystallography, NMR)로는 연구하기가 어려웠던 protein과 ligand간의 상호작용을 예측하여 이에 대한 정보를 제공할 수 있다. 하지만, 우선적으로 Molecular docking 시뮬레이션은 정확한 validation을 기반으로 진행되어야 신뢰할 수 있는 정보를 얻을 수 있다. 따라서 이번 연구에서는 EDISON에서 제공하는 Dock 프로그램과 일반적으로 잘 알려진 Glide, Autodock 프로그램으로 protein data bank(PDB)에서 제공하는 EGFR wild type cocrystal을 redocking하는 방식을 통하여 최상위 rank pose의 RMSD 값을 통한 validation 성능을 비교함으로써 어떤 프로그램이 EGFR과 ligand 간의 결합예측을 하는데 있어서 보다 더 정확한 결과를 낼 수 있는지 알아보고자 하였고 시뮬레이션 결과 Autodock에서 가장 우수한 결과 값을 보여주었다.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.4
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• pp.365-372
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• 2015

Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor $(NF)-{\kappa}B$, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.

• Journal of Ginseng Research
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• v.45 no.4
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• pp.465-472
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• 2021

Background: Ginseng can help regulate brain excitability, promote learning and memory, and resist cerebral ischemia in the central nervous system. Ginsenosides are the major effective compounds of Ginseng, but their protein targets in the brain have not been determined. Methods: We screened proteins that interact with the main components of ginseng (ginsenosides) by affinity chromatography and identified the 14-3-3 ζ protein as a potential target of ginsenosides in brain tissues. Results: Biolayer interferometry (BLI) analysis showed that 20(S)-protopanaxadiol (PPD), a ginseng saponin metabolite, exhibited the highest direct interaction to the 14-3-3 ζ protein. Subsequently, BLI kinetics analysis and isothermal titration calorimetry (ITC) assay showed that PPD specifically bound to the 14-3-3 ζ protein. The cocrystal structure of the 14-3-3 ζ protein-PPD complex showed that the main interactions occurred between the residues R56, R127, and Y128 of the 14-3-3 ζ protein and a portion of PPD. Moreover, mutating any of the above residues resulted in a significant decrease of affinity between PPD and the 14-3-3 ζ protein. Conclusion: Our results indicate the 14-3-3 ζ protein is the target of PPD, a ginsenoside metabolite. Crystallographic and mutagenesis studies suggest a direct interaction between PPD and the 14-3-3 ζ protein. This finding can help in the development of small-molecular compounds that bind to the 14-3-3 ζ protein on the basis of the structure of dammarane-type triterpenoid.