A novel method for fast and accurate prediction of ligand induced conformational changes in receptor active sites
About Induced Fit
The active site geometry of a protein complex depends heavily upon conformational changes induced by the bound ligand. However, resolving the crystallographic structure of a protein-ligand complex requires a substantial investment of time, and is frequently infeasible or impossible. Schrödinger's Induced Fit (IFD) protocol solves this problem by using Glide and Prime to exhaustively consider possible binding modes and the associated conformational changes within receptor active sites. The unique procedure allows chemists to quickly predict active site geometries with minimal expense, even for systems as challenging as hERG homology models.
The Induced Fit protocol begins by docking the active ligand with Glide. In order to generate a diverse ensemble of ligand poses, the procedure uses reduced van der Waals radii and an increased Coulomb-vdW cutoff, and can temporarily remove highly flexible side chains during the docking step. For each pose, a Prime structure prediction is then used to accommodate the ligand by reorienting nearby side chains. These residues and the ligand are then minimized. Finally, each ligand is re-docked into its corresponding low energy protein structures and the resulting complexes are ranked according to GlideScore. Accuracy is ensured by Glide's superior scoring function and Prime's advanced conformational refinement.
The Induced Fit methodology has been thoroughly refined in real-world research applications, and is readily used by novice and expert modelers alike. Maestro, the graphical user interface for all Schrödinger software, allows researchers to easily perform Induced Fit simulations and interpret the results. In addition to default settings suitable for a wide range of systems, the Induced Fit interface features advanced options that can be customized to solve more challenging cases. Calculations can be completed in a matter of hours on a desktop machine, or in as few as 30 minutes when distributed across multiple processors.
The table below illustrates the reliable performance of Schrödinger's Induced Fit protocol:
|RMSD of Top-Ranked Poses Returned by Induced Fit|
|Target||Receptor||PDB source of ligand structure||Docking RMSD before Induced Fit (Å)||Ligand RMSD after Induced Fit (Å)|
|Estrogen receptor||3ert||1err||2.3||1.4 (1.01)|
|PPAR - gamma||1fm9||2prg||9.1||1.8 (0.43)|
|PPAR - gamma||2prg||1fm9||9.8||3.0 (1.54)|
1 RMSD of 2nd ranked IFD structure, which has nearly identical composite score as the top ranked structure
2 Second round of IFD was performed because nearly isoenergetic structures were returned from the first round
3 RMSD excluding 10 atoms in the partially solvent exposed methyl-2-pyridinylamino tail of the ligand that has atoms with very high B-factors (>60 Å2)
4 RMSD excluding 13 atoms in the partially solvent exposed methylphenyloxazole tail of the ligand
5 RMSD excluding 6 atoms in the symmetric di-carboxylate that are flipped 180° in the IFD structure
The Receptor column lists the rigid receptors into which the ligands of other co-crystallized structures are inducing conformational changes. Prior to treatment with Induced Fit, docking results to the rigid receptor return either no poses or high RMSDs. Ligand poses improve dramatically as Induced Fit accurately predicts the active site geometry.
Validated across a variety of diverse systems, Schrödinger's Induced Fit protocol equips researchers with a highly efficient method for the accurate prediction of protein-ligand interactions.
Citations and Acknowledgements
Schrödinger Release 2017-1: Schrödinger Suite 2017-1 Induced Fit Docking protocol; Glide, Schrödinger, LLC, New York, NY, 2017; Prime, Schrödinger, LLC, New York, NY, 2017.
ö Farid, R.; Day, T.; Friesner, R. A.; Pearlstein, R. A., "New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies," Bioorg. & Med. Chem., 2006, 14, 3160-3173
ö Sherman, W.; Day, T.; Jacobson, M. P.; Friesner, R. A.; Farid, R., "Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects," J. Med. Chem., 2006, 49, 534-553
ö Sherman, W.; Beard, H. S.; Farid, R., "Use of an Induced Fit Receptor Structure in Virtual Screening," J. Med. Chem., 2004, 47, 1739–1749
ö "Prediction of Protein–Ligand Binding Poses via a Combination of Induced Fit Docking and Metadynamics Simulations"Clark, A.J.; Tiwary, P.; Borrelli, K.; Feng, S.; Miller, E.B.; Abel, R.; Friesner, R.A.; and Berne, B.J., J. Chem. Theory Comput., 2016, 12 (6), 2990–2998
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ö "A Computational Approach to Enzyme Design: Predicting ω-Aminotransferase Catalytic Activity Using Docking and MM-GBSA Scoring"Sirin, S.; Kumar, R.; Martinez, C.; Karmilowicz, M.J.; Ghosh, P.; Abramov, Y.A.; Martin, V.; Sherman, W., J. Chem. Inf. Model., 2014, 54(8), 2334-2346
ö "Consensus Induced Fit Docking (cIFD): Methodology, validation, and application to the discovery of novel Crm1 inhibitors"Kalid, O.; Warshaviak, D.T.; Shechter, S.; Sherman, W.; Shacham, S., J. Comput. Aided Mol. Des., 2012, 26, 1217–1228
"Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: Further structure–activity relationships, in vivo studies, and preliminary toxicity profiling"Gemma, S.; Camodeca, C.; Coccone, S.S.; Joshi, B.P.; Bernetti, M.; Moretti, V.; Brogi, S.; de Marcos, M.C.B.; Savini, L.; Taramelli, D.; Basilico, N.; Parapini, S.; Rottmann, M.; Brun, R.; Lamponi, S.; Caccia, S.; Guiso, G.; Summers, R.L.; Martin, R.E.; , J. Med. Chem., 2012, 55(15), 6948-6967
Schrödinger has made available the HERG homology model and one of the Induced Fit structures from the following publication:
Farid, R.; Day, T.; Friesner, R. A.; Pearlstein, R. A., "New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies", Bioorg. & Med. Chem., 2006, 14, 3160-3173.
Note: The structure 'HERG_HM_open.pdb' is the open form of the homology model that was used as the starting structure for the Induced Fit Docking (IFD) procedure described in the paper. In order to predict the binding mode for a particular HERG blocker or to produce a protein structure suitable for screening studies, it is recommended that our IFD procedure be used, starting from the provided homology model and a structure of the known blocker. We have also made available the Induced Fit structure with S-terfenadine bound ('HERG_IFD_S-terfenadine.pdb'), which is shown in Figure 6 of the above publication.