Elucidation of different inhibition mechanism of small chemicals on PtdInsP-binding domains using in silico docking experiments
- Authors
- Kim, Yonghwan; Yoon, Youngdae
- Issue Date
- 15-May-2014
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Phosphatidylinositides; Pleckstrin homology domain; Epsin1 N-terminal homology domain; In silico docking experiments; Surface plasmon resonance; Small chemicals
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.24, no.10, pp 2256 - 2262
- Pages
- 7
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- Volume
- 24
- Number
- 10
- Start Page
- 2256
- End Page
- 2262
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/10889
- DOI
- 10.1016/j.bmcl.2014.03.085
- ISSN
- 0960-894X
1464-3405
- Abstract
- Phosphatidylinositides, most negatively charged lipids in cellular membranes, regulate diverse effector proteins through the interaction with their lipid binding domains. We have previously reported inhibitory effect of small chemicals on the interaction between PtdIns(3,4,5)P-3 and Btk PH domain. Here, we report that the inhibitory effects of same sets of chemicals on Grp1 PH domain and epsin1 ENTH domain to elucidate diversity of inhibitory mechanisms upon different lipid binding domains. Among the chemicals, chemical 8 showed best inhibition in vitro assay for Grp1 PH domain and epsin1 ENTH domain, and then the interaction between small chemicals and lipid binding domains was further investigated by in silico docking experiments. As a result, it was concluded that the diverse inhibitory effects on different lipid binding domains were dependent on not only the number of interactions between small chemical and domain, but also additional interaction with positively charged surfaces as the secondary binding sites. This finding will help to develop lipid binding inhibitors as antagonists for lipid-protein interactions, and these inhibitors would be novel therapeutic drug candidates via regulating effector proteins involved in severe human diseases. (C) 2014 Elsevier Ltd. All rights reserved.
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