Ligand entry pathways in the ligand binding domain of PPARγ receptor

• Published in: FEBS letters Vol. 585; no. 16; pp. 2599 - 2603
• Main Authors: Aci-Sèche, Samia, Genest, Monique, Garnier, Norbert
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 19-08-2011; Wiley
• Subjects: Ligand entry pathway; Ligands; Molecular Dynamics Simulation; PPAR gamma - chemistry; PPAR gamma - metabolism; PPARγ; Protein Binding; Protein Structure, Tertiary; Targeted molecular dynamics; Thermodynamics; Targeted molecular dynamics; PPARγ; Ligand entry pathway; PPAR gamma
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2011.07.014

► Targeted molecular dynamics can drive the GW0072-PPARγ complex from an unbound form to the bound form. ► No energy barrier is observed during the entry process. ► This method may help in silico structure based drug design.
To address the question of ligand entry process, we report targeted molecular dynamics simulations of the entry of the flexible ionic ligand GW0072 in the ligand binding domain of the nuclear receptor PPARγ. Starting with the ligand outside the receptor the simulations led to a ligand docked inside the binding pocket resulting in a structure very close to the holo-form of the complex. The results showed that entry process is guided by hydrophobic interactions and that entry pathways are very similar to exit pathways. We suggest that TMD method may help in discriminating between ligands generated by in silico docking.