Discovery of novel benzophenone integrated derivatives as anti-Alzheimer's agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach

Abstract

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.

Fig 1

The homology built 3D structure of PSEN-1 is represented in (A). The structure assessment by Ramachandran plot is shown in (B).

Fig 2

The homology built 3D structure of PSEN-2 is represented in (A). The structure assessment by Ramachandran plot is shown in (B).

Fig 3

CASTp result of PSEN-1 protein A) Binding pocket (highlighted in red) of modelled protein and B) Residues in the sequence (red: α-helix, yellow: strand, pink: π-helix, cyan: turn, green: bend, grey: coil); active binding residues: highlighted in the middle with greyish blue.

Fig 4

CASTp result of PSEN-2 protein A) Binding pocket (highlighted in red) of modelled protein and B) Residues in the sequence (red:α-helix, yellow: strand, pink: π-helix, cyan: turn, green: bend, grey: coil); Active binding residues: highlighted in the middle with greyish blue.

Fig 5. Binding affinity, non-bonding interactions, and hydrogen bonds formed during the molecular docking simulation of PSEN-1.

Fig 6. Binding affinity, non-bonding interactions, and hydrogen bonds formed during the molecular docking simulation of PSEN-2.

Fig 7

Visualization of docking interaction of BID-16 and BID-19 (negative control) bound with PSEN-1 protein (A) atom type surface (B) 3D binding interaction of BID-16 (C) 3D binding interaction of BID-19 (highlighted in red) (D) 2D binding interaction of BID-16 (E) 2D binding interaction of BID-19 (highlighted in red).

Fig 8

Visualization of docking interaction of BID-16 and BID-20 (negative control) bound with PSEN-2 protein (A) atom type surface (B) 3D binding interaction of BID-16 (C) 3D binding interaction of BID-20 (highlighted in red) (D) 2D binding interaction of BID-16 (E) 2D binding interaction of BID-20 (highlighted in red).

Fig 9. Plot of the molecular dynamics simulations trajectories obtained after 100 ns interaction for BID-16 and BID-19 (negative control) bound with PSEN-1 protein.

(A) RMSD (B) RMSF (C) Rg (D) SASA, and (E) ligand hydrogen bonds; Green: protein backbone atoms, black: protein-BID-16 complex, red: protein-BID-19 complex (negative control).

Fig 10. Plot of the molecular dynamics simulations trajectories obtained after 100 ns interaction for BID-16 and BID-20 (negative control) bound with PSEN-2 protein.

(A) RMSD (B) RMSF (C) Rg (D) SASA, and (E) ligand hydrogen bonds; Green: protein backbone atoms, black: protein-BID-16 complex, red: protein-BID-20 complex (negative control).