scholarly journals Absolute Free Energy of Binding of Avidin/Biotin, Revisited

2012 ◽  
Vol 116 (23) ◽  
pp. 6628-6636 ◽  
Author(s):  
Ignacio J. General ◽  
Ralitsa Dragomirova ◽  
Hagai Meirovitch
Keyword(s):  
Free Energy ◽  
Free Energy Of Binding

Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

2017 ◽  
Vol 14 (10) ◽  
pp. 1122-1137 ◽  
Author(s):  
Nivedita Singh ◽  
Parameswaran Saravanan ◽  
M.S. Thakur ◽  
Sanjukta Patra
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Signal Transduction Pathway ◽  
Docking Study ◽  
Primary Objective ◽  
Cgmp Level ◽  
Active Site Residues ◽  
Aromatic Fragment ◽  
Docking Approach ◽  
Free Energy Of Binding

Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP. When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed. Objective: The primary objective of the present study was to develop new xanthine based inhibitors targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold. Methods: Manual designing and parallel molecular docking approach were used for the development of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were used for final validation of most promising compounds. Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A active site pocket with a significant interaction pattern. This was further validated by screening different factors such as free energy of binding, inhibition constant and interacting active site residues in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was found that compound 39-42 formed selective interaction towards PDE9A over other members of the PDE superfamily. Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best sites for substitution for the generation of potent PDE9A inhibitors.

scholarly journals Relative free energy of binding between antimicrobial peptides and SDS or DPC micelles

2009 ◽  
Vol 35 (10-11) ◽  
pp. 986-997 ◽  
Author(s):  
Abdallah Sayyed-Ahmad ◽  
Himanshu Khandelia ◽  
Yiannis N. Kaznessis
Keyword(s):  
Free Energy ◽  
Antimicrobial Peptides ◽  
Relative Free Energy ◽  
Free Energy Of Binding

scholarly journals Accurate calculation of the absolute free energy of binding for drug molecules

2016 ◽  
Vol 7 (1) ◽  
pp. 207-218 ◽  
Author(s):  
Matteo Aldeghi ◽  
Alexander Heifetz ◽  
Michael J. Bodkin ◽  
Stefan Knapp ◽  
Philip C. Biggin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Free Energy Calculations ◽  
Accurate Calculation ◽  
Energy Calculations ◽  
Thermodynamic Cycles ◽  
Drug Molecules ◽  
The Absolute ◽  
Free Energy Of Binding

Free energy calculations based on molecular dynamics and thermodynamic cycles accurately reproduce experimental affinities of diverse bromodomain inhibitors.

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