Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis
Abstract
:1. Introduction
2. Results and Discussion
2.1. Analysis of the PPARγ LBD and Ligand-Receptor Interactions
2.2. Pharmacophore Development
3. Experimental Section
3.1. PPARγ Structural and Activity Data
3.2. Preparation of the Protein Structures (Protonate 3D)
3.3. Analysis of the Ligand-Receptor Interactions
3.4. Superposition of the Complexes
3.5. Pharmacophore Development
4. Conclusions
Supplementary Information
ijms-15-07651-s001.pdfAcknowledgments
Conflicts of Interest
References
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Pharmacophore feature | Location | Interactions |
---|---|---|
F1: Don/Acc | Arm I | Participates in HB interactions (donor and acceptor) with residues His449 (H11) and Tyr473 (H12); responsible for the direct interaction with H12 and stabilises its active position |
F2: Acc | Arm I | Participates in HB interactions (acceptor) with Ser289 (H3), His323(H5), Tyr 327 (H5); responsible for the stabilization of H12 in an active position |
F3: Hyd/Aro | Arm I | Fits to the hydrophobic environment; stabilises the positions of F1 and F2 features |
F4: Don/Acc | Arm II | Can participate in HB interactions directly or mediated by water molecules with Ser342 (H5), Cys285 (H3) and Arg 288 (H3); stabilises the pose of the ligand into the pocket |
F5: Hyd/Aro | Arm II | Fits to the hydrophobic environment; stabilises the pose of the ligand into the pocket |
F6: Don/Acc | Arm I | Can participate in HB interactions mediated by water; stabilises the pose of the ligand into the pocket |
F7: Hyd/Aro | Arm I | Fits to the hydrophobic environment; stabilises the pose of the ligand into the pocket |
Complex PDB ID, [Ref.] | Ligand PDB ID | Pharmacophore features | EC50 (nM) | ||||||
---|---|---|---|---|---|---|---|---|---|
F1 | F2 | F3 | F4 | F5 | F6 | F7 | |||
1K74 [25] | 544 | + | + | + | + | + | + | + | 0.2–2.7 |
1FM9 [18] | 570 | + | + | + | + | + | + | + | 0.339–6 |
1FM6 [18] | BRL | + | + | + | + | + | − | − | 2.4–2880 |
3AN4 [26] | M7R | − | + | + | + | + | − | − | 3.6 |
3BC5 [27] | ZAA | + | − | + | + | + | + | − | 4 |
3IA6 [28] | UNT | + | + | + | + | + | − | − | 13 |
1I7I [29] | AZ2 | + | + | + | − | − | − | + | 13–3528 |
3G9E [30] | RO7 | + | + | + | + | + | − | − | 21 |
3AN3 [26] | M7S | − | + | + | + | + | − | − | 22 |
2ZNO [31] | S44 | − | + | + | + | + | − | − | 41–70 |
3GBK [32] | 2PQ | + | + | + | + | + | − | − | 50 |
3VJI [33] | J53 | − | + | + | − | + | − | − | 58 |
2F4B [34] | EHA | + | − | + | − | + | − | − | 70 |
2Q8S [35] | L92 | + | + | + | + | + | − | − | 140 |
1KNU [36] | YPA | + | + | + | + | + | − | + | 170 |
3FEJ [37] | CTM | + | + | + | − | + | − | + | 210 |
2HWR [38] | DRD | + | + | + | − | + | − | − | 210 |
2ATH [39] | 3EA | + | + | + | − | + | − | − | 230 |
2XKW [40] | P1B | + | + | + | + | + | − | − | 280 |
1NYX [41] | DRF | + | + | + | − | + | − | − | 570–600 |
2GTK [42] | 208 | + | + | + | + | + | − | + | 760 |
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Tsakovska, I.; Al Sharif, M.; Alov, P.; Diukendjieva, A.; Fioravanzo, E.; Cronin, M.T.D.; Pajeva, I. Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis. Int. J. Mol. Sci. 2014, 15, 7651-7666. https://doi.org/10.3390/ijms15057651
Tsakovska I, Al Sharif M, Alov P, Diukendjieva A, Fioravanzo E, Cronin MTD, Pajeva I. Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis. International Journal of Molecular Sciences. 2014; 15(5):7651-7666. https://doi.org/10.3390/ijms15057651
Chicago/Turabian StyleTsakovska, Ivanka, Merilin Al Sharif, Petko Alov, Antonia Diukendjieva, Elena Fioravanzo, Mark T. D. Cronin, and Ilza Pajeva. 2014. "Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis" International Journal of Molecular Sciences 15, no. 5: 7651-7666. https://doi.org/10.3390/ijms15057651