GW0072 

Targeted molecular dynamics simulations of the entry of GW0072, a macromolecular ligand with flexible ionic properties, into the ligand-binding domain of the nuclear receptor PPARc were performed. Starting from the apo-form, where the ligand is located outside the receptor, the simulation ultimately locks the ligand into the binding pocket, yielding a structure very close to the holo-form. The results show that the entry process is mainly guided by hydrophobic interactions, and that the entry and exit pathways are very similar. We suggest that the TMD approach may be useful in distinguishing ligands generated by in silico docking. To address the question of the ligand entry process, we report targeted molecular dynamics (TMD) simulations of the binding of the GW0072 ligand to the ligand-binding domain (LBD) of the peroxisome proliferator-activated receptor gamma (PPARc). PPARc is a member of the nuclear receptor superfamily and an important agent target for many diseases. We chose to study this complex because (i) GW0072 is a large ionic, highly flexible ligand that includes aliphatic chains and polar groups, and (ii) previous simulations have defined a possible escape pathway for this ligand. Starting from the apo-form of the receptor (PDB.ID 1PRG, chain A), with the ligand located outside, TMD simulations converged on a holo-form complex that is close to the target structure (PDB.ID 4PRG, chain A), defining a permeation pathway into the binding pocket that is very similar to the escape pathway. However, during the entry of GW0072 into the receptor (Fig. 5), the helices are very mobile, and once the ligand is placed in the pocket, AF-2 becomes more rigid during the remainder of the simulation (Fig. S1 in the Supplementary Materials). This finding is in good agreement with the observations of Oberfield et al. [12], suggesting that despite the absence of direct interaction with the ligand, the presence of the ligand in the binding site stabilizes an intermediate conformation of AF-2, which may be responsible for the property of GW0072 as a partial agonist.

614.84

C₃₇H₄₆N₂O₄S

321557-86-2

O=C(C1=CC=C(C=C1)CCCCN2[C@@H](S[C@H](C2=O)CC(N(CC3=CC=CC=C3)CC4=CC=CC=C4)=O)CCCCCCC)O

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• [1]. Ligand entry pathways in the ligand binding domain of PPARc receptor