Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

Abstract

Alzheimer's disease (AD), apparently the most widespread reason behind dementia, is delineated by a continuous cognitive weakening in the aged. During its progression, N-methyl-D-aspartate receptor (NMDAR) antagonists are known to play a pivotal part in the mechanisms of learning and memory. Since there is an unmet medical need for the treatment of AD, we aim to identify possible chemical compounds targeted toward N-methyl-D-aspartate receptors. Three-dimensional models are developed to unveil some of the essential characteristics of the N-methyl-D-aspartate receptors by using a collection of already discovered N-methyl-D-aspartate receptor inhibitors. This is followed by virtual screening, which results in novel chemical compounds having the potential to inhibit N-methyl-D-aspartate receptors. Molecular docking studies and analysis promulgated two lead compounds with a high LibDock score. The compounds are shortlisted based on high estimated activity, fit values, LibDock score, no violation of Lipinski's, and availability for procuring. Finally, the shortlisted compounds are tested by employing in vivo studies, which we further propose as potential NMDA inhibitors for treating AD.

Keywords: Alzheimer’s disease; Discovery Studio; N-methyl-D-aspartate; molecular docking.

Figure 1:

Pharmacophoric features identified from best hypothesis 1.

Figure 2:

A plot of actual versus estimated biological activity for training set compounds.

Figure 3:

Graph of 99% cat-scrambled correlation data. None of the outcome hypotheses has a higher correlation score than the initial (best) hypothesis.

Figure 4:

Graph of 99% cat-scrambled cost data. None of the outcome hypotheses has a higher correlation score than the initial (best) hypothesis.

Figure 5:

A plot of actual versus estimated biological activity for test set compounds.

Figure 6:

Pharmacophore mapping of most active compound of an external test set onto the chosen pharmacophore model (Hypo1).

Figure 7:

A plot of actual versus estimated biological activity for external test set compounds.

Figure 8:

(A) Interaction of HTS 00987 with Tyr214, Thr174, Pro170, His88, and Lys87 in the active site (Green dotted lines represent hydrogen bond interactions; pink dotted lines represent Van der Waals interaction). (B) Interaction of memantine with Ser131, Tyr282, Gly264, Ser260, Asp283, His127, and Arg292 in the active site (green dotted lines representing hydrogen bond interactions; pink dotted lines representing Van der Waals interaction).

Figure 9:

The schematic diagram of the eight-arm radial maze. The animals were tested in the RAM 30 min after the administration of inducing agent (diazepam).

Figure 10:

The effects of control (CMC), standard (memantine), and test (HTS 00987) on an eight-arm radial maze in diazepam-induced amnesia in mice: (A) Number of entries in the baited arm. (B) Duration in baited arms (in seconds). (C) Reference/WMEs. (D) Percentage of correct choices. The error bars correspond to the SD of the measurements.