Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer's Disease

Abstract

Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aβ) aggregation and impaired synaptic transmission, which makes the associated proteins, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of Rosmarinus officinalis, ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.

Keywords: AChE; Alzheimer’s disease; BACE I; Rosmarinus officinalis; Synapsin I, II, III; docking.

Figure 1

Chemical structures of bioactive constituents of R. officinalis. Structures were acquired from PubChem database.

Figure 2

Molecular docking interaction models of AChE (PDB ID: 4PQE) with donepezil and ursolic acid. 2D structures of the compounds are shown by line and stick models with the surrounding amino acids of AChE. The interactions are denoted by the following colors: hydrogen bonding interactions (green), alkyl bonds (pink) and bumps (red). AChE; Acetylcholinesterase.

Figure 3

Molecular docking interaction models of BACE 1 (PDB ID: 2WJO) with donepezil, ursolic acid and rosmarinic acid. 2D structures of the compounds are shown by line and stick models with the surrounding amino acids of BACE1. The interactions are denoted by the following colors: hydrogen-bonding interactions (green), alkyl bonds (purple) and bumps (red). BACE1; β-site amyloid precursor protein cleaving enzyme 1.

Figure 4

Molecular docking interaction models of synapsin I, II and III with donepezil and rosmarinic acid. 2D structures of the compounds are shown by line and stick models with the surrounding amino acids of synapsin I, II and III. The interactions are denoted by the following colors: hydrogen bonding interactions (green), carbon bonds (blue), alkyl bonds (purple) and bumps (red).

Figure 5

(I) RMSD plot of the bioactive compounds of R. officinalis with target proteins at 25 ns. (II) RMSF plot of AChE, BACE1, synapsin I, synapsin II and synapsin III with CA, RA, UA and donepezil respectively.

Figure 6

Binding free energies of bioactive compounds of R. officinalis against AChE, BACE1, synapsin I, synapsin II, and synapsin III with CA, RA, UA and donepezil, respectively.