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Abstract
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Article Information:
Assessment of Molecular Binding of Podophyllotoxin Analogues into ATPase Domain of Topoisomerase II Using Docking-MM-GB/SA Approach
Amiya Kumar Patel, Seema Patel and Pradeep Kumar Naik
Corresponding Author: Amiya Kumar Patel
Submitted: 2009 July, 26
Accepted: 2009 August, 17
Published: 2010 January, 05 |
Abstract:
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Synthetic analogues of Podophyllotoxin have been used to create efficient safer anticancer drugs.
One hundred twenty six analogues using combinatorial design with structural modifications of the scaffold
structure of podophyllotoxin are herein described. Molecular interaction and binding affinities with ATPase
domain of human DNA Topoisomerase II (TP-II) using docking-MM-GB/SA screening are illustrated. Results
showed that these analogues docked in a similar position and orientation on the ATPase domain of TP-II. A
linear correlation (r2 = 0.5707) was observed between the calculated free energy of binding (FEB) and
experimental IC50 for the inhibitors, suggesting that theses inhibitors bind weakly with TP-II. Three H-bonds
between podophyllotoxin analogues (trans lactones) and DNA topoisomerase II were observed. The vdW
energy estimated by generalized born/surface area (GB/SA) plays an important role in the binding affinity of
podophyllotoxin analogues. Out of 126 derivatives, lactones tetralines were found to be the most potent in
general in comparison with the non-lactones tetralines and non-lactones cyclolignans. This work addresses to
modify the lactone moiety and prepare synthetic analogues with heteroatoms at different positions of the
podophyllotoxin and further screening for a successful candidate drug in a computer-aided rational drug design.
Key words: ATPase domain, DNA Topoisomerase II, free energy of binding (FEB), FlexX, glide, GOLD, podophyllotoxin
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Cite this Reference:
Amiya Kumar Patel, Seema Patel and Pradeep Kumar Naik, . Assessment of Molecular Binding of Podophyllotoxin Analogues into ATPase Domain of Topoisomerase II Using Docking-MM-GB/SA Approach. Current Research Journal of Biological Sciences, (1): Page No: 13-23.
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ISSN (Online): 2041-0778
ISSN (Print): 2041-076X |
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