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Molecules 2014, 19(5), 6609-6622; doi:10.3390/molecules19056609

In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site

Chemistry, Centre for Chemical Biology, The University of Newcastle, University Drive Callaghan, NSW 2308, Australia
Author to whom correspondence should be addressed.
Received: 20 March 2014 / Revised: 6 May 2014 / Accepted: 14 May 2014 / Published: 22 May 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa- 2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors. View Full-Text
Keywords: bolinaquinone; clathrin terminal domain; flexible docking; linear interaction energy bolinaquinone; clathrin terminal domain; flexible docking; linear interaction energy

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Abdel-Hamid, M.K.; McCluskey, A. In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site. Molecules 2014, 19, 6609-6622.

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