• Bulletin of the Korean Chemical Society
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• v.32 no.1
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• pp.251-262
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• 2011

Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : $r^2$ = 0.955, $q^2$ = 0.781, $r^2_{pred}$ = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.

• Clinical and Experimental Reproductive Medicine
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• v.26 no.2
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• pp.287-291
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• 1999

Dopamine agonists are commonly used in the medical treatment of prolactinomas. Bromocriptine has been the most widely used ergot derivative for two decades. Its oral administration, at a daily dose of $2.5{\sim}7.5mg$, restored normal gonadal function and normoprolactinemia in about 80% of patients. Nevertheless, a subset of patients could not achieve normal prolactin levels or resume normal gonadal function despite $15{\sim}30mg$/day bromocriptine for at least 6 months. Subsequently, these prolactinomas were consedered to be resistant to bromocriptine. The percentage of bromocriptine - resistant prolactinoma patients reported in the literature varies between 5 and 17% according to the series. Patients with bromocriptine resistance or bromocriptine intolerance have, however, been treated with other dopamine agonists, such as lysuride, pergolide, cabergoline, or quinagolide. Until cabergoline recently gained a product licence in the UK, there was no alternative dopamine agonist with a licence for this purpose. Quinagolide (CV $205{\sim}502$, Norprolac, Sandoz) is a nonergot dopamine agonist with improved selectivity for the D2 receptor, designed to retain the active pharmacophore of bromocriptine without the ergot moiety that might be responsible for side - effects. We have experienced a case of bromocriptine resistant hyperprolactinemia which was reponsive to pergolide. So we report this case with a brief review of literatures.

• Bulletin of the Korean Chemical Society
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• v.35 no.4
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• pp.1073-1076
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• 2014

In attempt to lead compounds exhibiting both insecticidal and fungicidal activities, a series of O-benzyl oximeether derivatives were designed and synthesized by introducing ${\beta}$-methoxyacrylate pharmacophore into a scaffold. The insecticidal activity against Aphis fabae and the fungicidal activity against Erysiphe graminis were screened. The title compounds exhibited remarkable insecticidal and fungicidal activities. The most potent compound 6d was identified. Its insecticidal $LC_{50}$ against A. fabae is 6.4 mg/L, which is lower than that of chlorfenapyr (19.4 mg/L) and even close to the level of imidacloprid (4.8 mg/L). Its fungicidal $EC_{90}$ in preventive and curative treatment against E. graminis are 2.2 and 4.8 mg/L, respectively, which are lower than azoxystrobin (7.0 and 5.9 mg/L). These results indicate that compound 6d can be considered as a lead for further developing new O-benzyl oxime-ether typed candidates with both fungicidal and insecticidal activities.

• Molecules and Cells
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• v.43 no.3
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• pp.222-227
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• 2020

Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro. The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.

• Journal of Microbiology and Biotechnology
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• v.32 no.10
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• pp.1262-1274
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• 2022

Cholangiocarcinoma (CCA) is a complex and refractor type of cancer with global prevalence. Several barriers remain in CCA diagnosis, treatment, and prognosis. Therefore, exploring more biomarkers and therapeutic drugs for CCA management is necessary. CCA gene expression data was downloaded from the TCGA and GEO databases. KEGG enrichment, GO analysis, and protein-protein interaction network were used for hub gene identification. miRNA were predicted using Targetscan and validated according to several GEO databases. The relative RNA and miRNA expression levels and prognostic information were obtained from the GEPIA. The candidate drug was screened using pharmacophore-based virtual screening and validated by molecular modeling and through several in vitro studies. 301 differentially expressed genes (DEGs) were screened out. Complement and coagulation cascades-related genes (including AHSG, F2, TTR, and KNG1), and cell cycle-related genes (including CDK1, CCNB1, and KIAA0101) were considered as the hub genes in CCA progression. AHSG, F2, TTR, and KNG1 were found to be significantly decreased and the eight predicted miRNA targeting AHSG, F2, and TTR were increased in CCA patients. CDK1, CCNB1, and KIAA0101 were found to be significantly abundant in CCA patients. In addition, Molport-003-703-800, which is a compound that is derived from pharmacophores-based virtual screening, could directly bind to CDK1 and exhibited anti-tumor activity in cholangiocarcinoma cells. AHSG, F2, TTR, and KNG1 could be novel biomarkers for CCA. Molport-003-703-800 targets CDK1 and work as potential cell cycle inhibitors, thereby having potential for consideration for new chemotherapeutics for CCA.

• Biomolecules & Therapeutics
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• v.31 no.3
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• pp.312-318
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• 2023

The natural flavonoid macakurzin C (1) exhibited adiponectin biosynthesis-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells and its molecular mechanism was directly associated with a pan-peroxisome proliferator-activated receptor (PPAR) modulator affecting all three PPAR subtypes α, γ, and δ. In this study, increases in adiponectin biosynthesis-inducing activity by macakurzin C derivatives (2-7) were studied. The most potent adiponectin biosynthesis-inducing compound 6, macakurzin C 3,5-dimethylether, was elucidated as a dual PPARα/γ modulator. Compound 6 may exhibit the most potent activity because of the antagonistic relationship between PPARδ and PPARγ. Docking studies revealed that the O-methylation of macakurzin C to generate compound 6 significantly disrupted PPARδ binding. Compound 6 has therapeutic potential in hypoadiponectinemia-related metabolic diseases.