Assessing protein-ligand binding modes with computational tools: the case of PDE4B
| Autor: | Viktorya Aviyente, E. Demet Akten, Gérald Monard, Gülşah Çifci |
|---|---|
| Přispěvatelé: | Akten, Ebru Demet |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Logarithm PDE4B Protein Conformation Quantitative Structure-Activity Relationship IC50 Molecular Dynamics Simulation Molecular dynamics Ligands 01 natural sciences Small Molecule Libraries 03 medical and health sciences Computational chemistry 0103 physical sciences Drug Discovery Molecule Humans Physical and Theoretical Chemistry Mathematics Discrete mathematics Binding Sites MM-GB/SA 010304 chemical physics Molecular Structure AutoDock Computer Science Applications Cyclic Nucleotide Phosphodiesterases Type 4 Molecular Docking Simulation 030104 developmental biology Linear relationship Molecular docking Thermodynamics Free energies Phosphodiesterase 4 Inhibitors Rolipram Protein ligand Protein Binding |
| Popis: | In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC[Formula: see text] values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC[Formula: see text] values [[Formula: see text](IC[Formula: see text])] and their calculated binding free energies ([Formula: see text]). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between [Formula: see text](IC[Formula: see text]) and the lowest [Formula: see text] is achieved with [Formula: see text]. |
| Databáze: | OpenAIRE |
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