Single or Multiple Access Channels to the CYP450s Active Site? An Answer from Free Energy Simulations of the Human Aromatase Enzyme

2017 ◽  
Vol 8 (9) ◽  
pp. 2036-2042 ◽  
Author(s):  
Alessandra Magistrato ◽  
Jacopo Sgrignani ◽  
Rolf Krause ◽  
Andrea Cavalli
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Multiple Access ◽  
Multiple Access Channels ◽  
Human Aromatase ◽  
Energy Simulations

Free Energy Simulations of Active-Site Mutants of Dihydrofolate Reductase

2014 ◽  
Vol 119 (3) ◽  
pp. 906-916 ◽  
Author(s):  
Dvir Doron ◽  
Vanja Stojković ◽  
Lokesh Gakhar ◽  
Alexandra Vardi-Kilshtain ◽  
Amnon Kohen ◽  
...  
Keyword(s):  
Free Energy ◽  
Dihydrofolate Reductase ◽  
Active Site ◽  
Energy Simulations ◽  
Active Site Mutants

scholarly journals Role of the Active Site Guanine in theglmSRibozyme Self-Cleavage Mechanism: Quantum Mechanical/Molecular Mechanical Free Energy Simulations

2015 ◽  
Vol 137 (2) ◽  
pp. 784-798 ◽  
Author(s):  
Sixue Zhang ◽  
Abir Ganguly ◽  
Puja Goyal ◽  
Jamie L. Bingaman ◽  
Philip C. Bevilacqua ◽  
...  
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Quantum Mechanical ◽  
Energy Simulations

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

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.

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