scholarly journals Using Free Energy of Binding Calculations To Improve the Accuracy of Virtual Screening Predictions

2011 ◽  
Vol 51 (7) ◽  
pp. 1648-1655 ◽  
Author(s):  
Robert D. Malmstrom ◽  
Stanley J. Watowich
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Free Energy Of Binding

scholarly journals Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

2020 ◽  
Vol 19 (6) ◽  
pp. 1255-1261
Author(s):  
Shazi Shakil ◽  
Adel M Abuzenadah ◽  
Suzan M. Attar ◽  
Omar Fathaldin ◽  
Rajaa Al-Raddadi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Free Energy ◽  
Virtual Screening ◽  
Thymidylate Synthase ◽  
Molecular Descriptors ◽  
Amino Acid Residues ◽  
Methotrexate Interaction ◽  
Inhibitor Design ◽  
Interaction Site ◽  
Free Energy Of Binding

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screening

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 Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase

ACS Omega ◽  
2016 ◽  
Vol 1 (3) ◽  
pp. 435-447 ◽  
Author(s):  
Baofeng Zhang ◽  
Michael P. D’Erasmo ◽  
Ryan P. Murelli ◽  
Emilio Gallicchio
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Hiv 1

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

Identification of Highly Potent Protein Kinase C-Related Kinase 1 Inhibitors by Virtual Screening, Binding Free Energy Rescoring, and in vitro Testing

ChemMedChem ◽  
2016 ◽  
Vol 11 (18) ◽  
pp. 2084-2094 ◽  
Author(s):  
Inna Slynko ◽  
Karin Schmidtkunz ◽  
Tobias Rumpf ◽  
Susan Klaeger ◽  
Stephanie Heinzlmeir ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
In Vitro Testing ◽  
Kinase C

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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