Probing the intermolecular interactions, binding affinity, charge density distribution and dynamics of silibinin in dual targets AChE and BACE1: QTAIM and molecular dynamics perspective.

Alzheimer's disease (AD) is the grievous neurodegenerative disorder. Reportedly, many enzymes are responsible for this disease, in which notably, acetylcholinesterase (AChE) and ß-secretase (BACE1) are largely involved for AD. An experimental study reports that silibinin molecule inhibits both AChE and BACE1 enzymes. Present study aims to understand the dual binding mechanism of silibinin in the active site of AChE and BACE1 from the intermolecular interactions, conformational flexibility, charge density distribution, binding energy and the stability of molecule. To obtain the above information, the molecular docking, molecular dynamics (MD) and QTAIM (quantum theory of atoms in molecules) calculations have been performed. The molecular docking reveals that silibinin molecule is forming strong and weak intermolecular interactions with the catalytic site of both enzymes. The QTAIM analysis for the binding pockets of both complexes shows the charge density distribution of intermolecular interactions. The electrostatic potential map displays the electronegative/positive regions at the interaction zone of silibinin with AChE and BACE1 complexes. The MD simulation confirms that the silibinin molecule is stable in the active site of AChE and BACE1 enzymes. The binding free energies of silibinin with both enzymes are more favorable to have the interactions.Communicated by Ramaswamy H. Sarma.

Binding studies of known molecules with acetylcholinesterase and bovine serum albumin: A comparative view.

The interactions between selected molecules (piperine, tacrine, curcumin and silibinin) and proteins (acetylcholinesterase and bovine serum albumin) were investigated by Fluorescence spectroscopy, molecular docking, molecular dynamics, free energy calculation and non-covalent interaction analysis. These binding characteristics are of huge interest for understanding pharmacokinetic mechanism of the target molecules. The steady-state emission spectrum results showed that presence of static quenching mode for piperine, tacrine, curcumin, silibinin molecules with BSA and AChE complexes separately and this excitation-emission matrix analysis suggest that formation of ground-state complex between piperine, tacrine, curcumin, silibinin drugs and both BSA, AChE protein molecules. And, the binding model from molecular docking analysis of both BSA and AChE with these molecules clearly displayed non-covalent interactions (hydrogen bonding and hydrophobic interactions) which played a significant role in the binding mechanism. Further, the protein-ligand complexes are subjected to molecular dynamics and binding free energy calculation to confirm the stability of the molecule in the active site of BSA and AChE. The NCI (non-covalent interaction) approach supports to visualize the iso-surface of the reduced density gradient of such interactions between protein and ligands.

Discovery of new potential triplet acting inhibitor for Alzheimer's disease via X-ray crystallography, molecular docking and molecular dynamics.

The most common brain disorder of late life is Alzheimer's disease (AD), which is highly complicating dementia. There are several drug targets which are reported to control the severe level of AD; notably, acetylcholinesterase, ß-Secretase and glycogen synthase kinase enzymes are approached as a good drug targets for AD. Hence, the present study mainly focused to discover newly synthesized molecule (7-propyl-6H-pyrano[3,2-c:5,6-c']dichromene-6,8(7H)-dione) as a potential triplet acting drug for above said enzymes through the analysis of X-ray crystallography, molecular docking, molecular dynamics and quantum chemical calculation. The target drug molecule was crystallized in the monoclinic crystal structure with P21/n space group. The structure was solved by SHELXS and refined by SHELXL. The crystal packing is stabilized by C - H···O type of interactions. Further, the induced fit docking shows that the molecule has high docking score, glide energy, favorable hydrogen bonding and hydrophobic interactions on the protein targets. The molecular dynamics simulation was performed to understand the stability of the molecule in the presence of active site environment. Finally, quantum chemical calculation has been carried out for the molecule in gas phase and for the corresponding molecule lifted from the active site region. The structural comparison between gas phase and active site helps to understand the conformational modification of the molecule in the active site. Communicated by Ramaswamy H. Sarma.