کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443577 692737 2010 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A comprehensive structure–activity analysis of protein kinase B-alpha (Akt1) inhibitors
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
A comprehensive structure–activity analysis of protein kinase B-alpha (Akt1) inhibitors
چکیده انگلیسی

Protein kinase B (PKB, also known as Akt) belongs to the AGC subfamily of the protein kinase superfamily. Akt1 has been reported as a central player in regulation of metabolism, cell survival, motility, transcription and cell-cycle progression, among the signalling proteins that respond to a large variety of signals. In this study an attempt was made to understand structural requirements for Akt1 inhibition using conventional QSAR, k-nearest neighbour QSAR and novel GQSAR methods. With this intention, a wide variety of structurally diverse Akt1 inhibitors were collected from various literature reports. The conventional QSAR analyses revealed the key role of Baumann's alignment independent topological descriptors along with other descriptors such as the number of hydrogen bond acceptors, hydrogen bond donors, rotatable bonds and aromatic oxygen (SaaOcount) along with molecular branching (chi3Cluster), alkene carbon atom type (SdsCHE-index) in governing activity variation. Further, the GQSAR analyses show that chemical variations like presence of hetero-aromatic ring, flexibility, polar surface area and fragment length present in the hinge binding fragment (in the present case fragment D) are highly influential for achieving highly potent Akt1 inhibitors. In addition, this study resulted in a k-nearest neighbour classification model with three descriptors suggesting the key role of oxygen (SssOE-index) and aromatic carbon (SaaCHE-index and SaasCE-index) atoms electro-topological environment that differentiate molecules binding to Akt1 kinase or PH domain. The developed models are interpretable, with good statistical and predictive significance, and can be used for guiding ligand modification for the development of potential new Akt1 inhibitors.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 28, Issue 7, April 2010, Pages 683–694
نویسندگان
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