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PKD1 3D Structure Model and Docking Studies for New PKD Inhibitors

Xu, Qi (2013) PKD1 3D Structure Model and Docking Studies for New PKD Inhibitors. Master's Thesis, University of Pittsburgh. (Unpublished)

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Protein kinase Ds (PKDs) are diacylglycerol (DAG)-regulated serine/threonine protein kinases. In intact cells, PKDs are key mediators in cellular processes pertaining to multiple diseases, including cancer, heart diseases, angiogenesis and immune dysfunctions. A number of the novel, potent, and structurally diverse ATP-competitive PKD inhibitors have been reported to selectively modulate the PKD activity and thus, to achieve a potential therapeutic effect on related diseases. Due to a lack of the crystal structure, we have constructed a 3D structure of the human PKD1 protein by using homology modeling. Then, by using our established protein docking protocol, we docked novel PKD inhibitory small molecules and found the hit compounds exhibiting higher binding scores with reasonable binding mode in comparison with the reported active PKD1 inhibitors. Also, we calculated both 2D and 3D molecular similarity between our identified compounds and previously reported PKD1 inhibitors. Moreover, we predicted the possible off-targets of our compounds and our prediction has been validated through a topomer similarity study. In this study, we demonstrated that computational tools, i.e., docking and molecular similarity calculation can be applied to explore the PKD1/inhibitor interactions. In addition, the docking studies and the detailed docking poses provide insight for better understanding of the possible mechanism of a bioactive PKD1 inhibitor in order to guide future optimization for new drug design and discovery.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorFolan, Maggiefolanm@pitt.eduFOLANM
Committee MemberXie, Xiangqunxix15@pitt.eduXIX15
Committee MemberWang, Lirongliw30@pitt.eduLIW30
Date: 29 August 2013
Date Type: Publication
Defense Date: 7 August 2013
Approval Date: 29 August 2013
Submission Date: 26 August 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 40
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: PKD1, homology modeling, small molecule, docking, molecular similarity
Date Deposited: 29 Aug 2013 20:30
Last Modified: 15 Nov 2016 14:15


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