Browsing by Author "Wu, Su-Ying"

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Design and Structural Analysis of Novel Pharmacophores for Potent and Selective Peroxisome Proliferator-activated Receptor gamma Agonists
(2009-04-23)
Lin, Chia-Hui
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Peng, Yi-Hui
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Coumar, Mohane Selvaraj
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Chittimalla, Santhosh Kumar
;
Liao, Chun-Chen
Utilizing medicinal chemistry design strategies Such as benzo splitting and ring expansion, we converted PPAR alpha/gamma dual agonist 1 to selective PPAR gamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPAR gamma receptor. with 80- to 100-fold PPAR gamma selectivity over PPAR alpha receptor. X-ray cocrystal studies in PPAR gamma and modeling studies in PPAR alpha give molecular insights for the improved PPAR gamma potency and selectivity for 19 when compared to 1.
Development of an Anti-Influenza Drug Screening Assay Targeting Nucleoproteins with Tryptophan Fluorescence Quenching
(1970-01-01)
Hung, Hui-Chen
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Liu, Chia-Lin
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Hsu, John T. -A.
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Horng, Jim-Tong
;
Fang, Ming-Yu
"Recent studies have shown that NP (nucleoprotein), which possesses multiple functions in the viral life cycle, is a new potential anti-influenza drug target. NP inhibitors reliably induce conformational changes in NPs, and these changes may confer inhibition of the influenza virus. The six conserved tryptophan residues in NP can be used as an intrinsic probe to monitor the change in fluorescence of the tryptophan residues in the protein upon binding to an NP inhibitor. In the present study, we found that the fluorescence of recombinant NP proteins was quenched following the binding of available NP inhibitors (such as nucleozin) in a concentration- and time-dependent manner, which suggests that the inhibitor induced conformational changes in the NPs. The minimal fluorescence-quenching effect and weak binding constant of nucleozin to the swine-origin influenza virus H1N1pdm09 (SOIV) NP revealed that the SOIV is resistant to nucleozin. We have used the fluorescence-quenching property of tryptophans in NPs that were bound to ligands in a 96-well-plate-based drug screen to assess the ability of promising small molecules to interact with NPs and have identified one new anti-influenza drug, CSV0C001018, with a high SI value. This convenient method for drug screening may facilitate the development of antiviral drugs that target viruses other than the influenza virus, such as HIV and HBV."
Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification
(2010-07-08)
Coumar, Mohane Selvaraj
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Chu, Chang-Ying
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Lin, Cheng-Wei
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Shiao, Hui-Yi
;
Ho, Yun-Lung
A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit la was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit Is, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.
Identification, SAR Studies, and X-ray Co-crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor
(2010-02-01)
Coumar, Mohane Selvaraj
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Tsai, Ming-Tsung
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Chu, Chang-Ying
;
Uang, Biing-Jiun
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Lin, Wen-Hsing
Here in we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy with IC(50) values ranging from similar to 300 nm to similar to 15 mu m, by testing only 133 compounds from a database of similar to 125 000 compounds. Structure activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nm toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.
Structural Basis for the Improved Potency of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
(2010-10-04)
Peng, Yi-Hui
;
Coumar, Mohane Selvaraj
;
Leou, Jiun-Shyang
;
Wu, Jian-Sung
;
Shiao, Hui-Yi
The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPAR gamma activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPAR gamma EC(50) of 10 nm. Compound 15 showed the most potent PPAR gamma agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPAR gamma; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPAR gamma.
Structural Basis for the Improved Potency of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
(2010-10-04)
Peng, Yi-Hui
;
Coumar, Mohane Selvaraj
;
Leou, Jiun-Shyang
;
Wu, Jian-Sung
;
Shiao, Hui-Yi
The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPAR gamma activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPAR gamma EC(50) of 10 nm. Compound 15 showed the most potent PPAR gamma agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPAR gamma; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPAR gamma.