Abstract
The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r2 = 0.928–0.988, = 0.894–0.954, RMSE = 0.002–0.412, s = 0.001–0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967, = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.
Highlights
N-methyl-D-aspartate receptor (NMDAR) are heteromeric assemblies of GluN1, GluN2, and GluN3 subunits, which were previously named as NR1, NR2, and NR3, respectively[4]
The objective of this study was to accurately model the ligand binding to the NMDAR subunit GluN1 by this novel support vector machine (SVM)-Pose/ SVM-Score combinatorial ensemble docking scheme to facilitate drug discovery to find novel therapeutics for the potential treatment of neurological disorder
The docking calculations based on the 5,7DCKA bound crystal structure (PDB: chain B of 1PBQ) yielded root mean square deviation (RMSD) values between 0.2 Å to 0.6 Å and an average RMSD of 0.43 Å for the 30 docked poses after 10 docking runs
Summary
NMDARs are heteromeric assemblies of GluN1, GluN2, and GluN3 subunits, which were previously named as NR1, NR2, and NR3, respectively[4]. NMDARs are highly flexible per se as illustrated by published crystal structures, namely GluN1 in co-complexes with glycine (PDB code: 1PB7), 5,7-dichlorokynurenic acid (DCKA) (PDB code: 1PBQ), and cycloleucine (PDB code: 1Y1M)[27,28]. When superimposed, these proteins show substantial structural discrepancies as displayed by Fig. 1, in which protein structures excerpted from co-complex structures were aligned, especially residues Thr[126], Arg[131], Ser[180], and Asp[224] that constitute the putative binding pocket and contribute to the plastic nature of GluN1. Ensemble docking, which is carried out by placing a ligand into several target structures and selecting the best fit pose by score or root mean square deviation (RMSD) values if applicable[34], seems to be a plausible alternative since it has been demonstrated that ensemble docking performs better than docking with a single protein structure[35]
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