Evaluating the Performance of MM/PBSA for Binding Affinity Prediction Using G Protein-Coupled Receptor Crystal Structures
-
1
Taylor's University, School of Pharmacy, Malaysia
-
2
University of Nottingham Malaysia Campus, School of Pharmacy, Malaysia
Background
The diverse G protein-coupled receptors (GPCRs) are major drug targets. The recently solved GPCR crystal structures offer opportunities to utilize various structure-based computational methods for drug design. Among these methods is Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA). As an end-state method, MM/PBSA provides a compromise of speed and accuracy between docking and free energy perturbation methods in predicting binding free energies. In this study, we evaluated the performance of MM/PBSA, which has been shown to be system-specific, using GPCR crystal structures.
Methods
Crystal structures of 15 Class A GPCRs were obtained from the Protein Data Bank. For each structure, a set of ligands with similar scaffold to the co-crystallized ligand and pKi values ranging from 5-10 were obtained from the ChEMBL database. The ligands were docked into the structures using Schrödinger’s Induced Fit Docking protocol. Molecular dynamics simulations were then performed using GROMACS with the AMBER ff99SB*-ILDN force field. MM/PBSA calculations were subsequently performed using g_mmpbsa, with the solute dielectric constants varied between 1, 2 and 4 to obtain the best correlation.
Results
The Pearson (rp) and Spearman (rs) correlations obtained between the MM/PBSA-predicted and experimental binding free energies ranged from -0.23-0.78 and -0.32-0.79 respectively. With the exception of a single target (5XRA: rp=0.78, rs=0.79), correlations produced by MM/PBSA were generally poor. MM/PBSA improved the correlations in only 7 out of 15 targets when compared to docking scores, which provided correlations in the range of rp -0.43-0.43 and rs -0.44-0.50.
Conclusion
The performance of MM/PBSA in predicting binding free energies using GPCR crystal structures remains relatively weak overall, but may provide good predictions for certain targets and offer marginal improvements over docking scores for some others. When using MM/PBSA to predict binding free energies of GPCR ligands, validation of the method for each target is therefore recommended.
Keywords:
MM/PBSA,
GPCR,
binding free energy,
Induced fit docking,
molecular dynamics
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Poster Presentation
Topic:
Miscellaneous
Citation:
Yau
M,
Emtage
A and
Loo
JS
(2019). Evaluating the Performance of MM/PBSA for Binding Affinity Prediction Using G Protein-Coupled Receptor Crystal Structures.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2018.63.00052
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
27 Sep 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Dr. Jason S Loo, Taylor's University, School of Pharmacy, Subang Jaya, Malaysia, jasonsiauee.loo@taylors.edu.my