Title:Fetzima (levomilnacipran), a Drug for Major Depressive Disorder as a Dual Inhibitor for Human Serotonin Transporters and Beta-Site Amyloid Precursor Protein Cleaving Enzyme-1
Volume: 13
Issue: 8
Author(s): Syed Mohd. Danish Rizvi, Sibhghatulla Shaikh, Mahiuddin Khan, Deboshree Biswas, Nida Hameed and Shazi Shakil
Affiliation:
Keywords:
Alzheimer's disease, major depressive disorder, fetzima, beta-site amyloid precursor protein cleaving enzyme-1,
serotonin transporters.
Abstract: Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors
which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid
precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting
target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug
Administration approved antidepressant drug named ‘Fetzima’ with BACE-1 and SERT. Fetzima is chemically known as
levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. ‘Autodock 4.2’ was
used for docking study. The free energy of binding (ΔG) values for ‘levomilnacipran-SERT’ interaction and
‘levomilnacipran-BACE1’ interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was
found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during
‘levomilnacipran-SERT’ interaction. In the case of ‘levomilnacipran-BACE1’ interaction, levomilnacipran interacted with
two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the
cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima
(levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future
dual therapy against depression and AD. It is an established fact that development of AD is associated with Major
Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be
particularly beneficial.
