کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1363628 | 981518 | 2007 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1 Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1](/preview/png/1363628.png)
A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-XL, and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-XL, and Bcl-w, and a set of inhibitors with varied selectivity to Bcl-2, Bcl-XL, and Bcl-w proteins have been identified. Molecular modeling of the interaction of the BHI-1 based analogues with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-XL, and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for anti-apoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-XL, and Bcl-w by targeting the non-conserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling-aided rational development of BHI-1 based selective inhibitor for anti-apoptotic Bcl-2 proteins is underway.
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Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 5, 1 March 2007, Pages 2167–2176