Pertubations in the Free Energy and Enthalpy of Ionization of Histidine-159 at the Active Site of Papain As Determined by Fluorescence Spectroscopy

Biochemistry ◽  
1981 ◽  
Vol 20 (1) ◽  
pp. 52-58 ◽  
Author(s):  
Frederick Johnson ◽  
Sidney Lewis ◽  
Jules Shafer
Keyword(s):  
Free Energy ◽  
Fluorescence Spectroscopy ◽  
Active Site ◽  
Enthalpy Of Ionization

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 Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 983 ◽  
Author(s):  
Diana Morales-Jadán ◽  
José Blanco-Salas ◽  
Trinidad Ruiz-Téllez ◽  
Francisco Centeno
Keyword(s):  
Free Energy ◽  
Active Site ◽  
In Silico ◽  
Binding Free Energy ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Physiological Importance ◽  
Promising Tool ◽  
Binding Pockets ◽  
Simulation Results

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.

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 active site conformational changes in photocycle activation of the AppA BLUF photoreceptor

2017 ◽  
Vol 114 (7) ◽  
pp. 1480-1485 ◽  
Author(s):  
Puja Goyal ◽  
Sharon Hammes-Schiffer
Keyword(s):  
Electron Transfer ◽  
Free Energy ◽  
Excited State ◽  
Charge Transfer ◽  
Conformational Changes ◽  
Ground State ◽  
Active Site ◽  
Locally Excited ◽  
Proton Relay ◽  
Locally Excited State

Blue light using flavin adenine dinucleotide (BLUF) proteins are essential for the light regulation of a variety of physiologically important processes and serve as a prototype for photoinduced proton-coupled electron transfer (PCET). Free-energy simulations elucidate the active site conformations in the AppA (activation of photopigment and puc expression) BLUF domain before and following photoexcitation. The free-energy profile for interconversion between conformations with either Trp104 or Met106 closer to the flavin, denoted Trpin/Metout and Trpout/Metin, reveals that both conformations are sampled on the ground state, with the former thermodynamically favorable by ∼3 kcal/mol. These results are consistent with the experimental observation of both conformations. To analyze the proton relay from Tyr21 to the flavin via Gln63, the free-energy profiles for Gln63 rotation were calculated on the ground state, the locally excited state of the flavin, and the charge-transfer state associated with electron transfer from Tyr21 to the flavin. For the Trpin/Metout conformation, the hydrogen-bonding pattern conducive to the proton relay is not thermodynamically favorable on the ground state but becomes more favorable, corresponding to approximately half of the configurations sampled, on the locally excited state. The calculated energy gaps between the locally excited and charge-transfer states suggest that electron transfer from Tyr21 to the flavin is more facile for configurations conducive to proton transfer. When the active site conformation is not conducive to PCET from Tyr21, Trp104 can directly compete with Tyr21 for electron transfer to the flavin through a nonproductive pathway, impeding the signaling efficiency.

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
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