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.
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.
authors.forename: Syed Mohd Danish
authors.initials: SM
authors.lastname: Rizvi
authors.forename: Sibhghatulla
authors.initials: S
authors.lastname: Shaikh
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Khan
authors.forename: Deboshree
authors.initials: D
authors.lastname: Biswas
authors.forename: Nida
authors.initials: N
authors.lastname: Hameed
authors.affiliation: Department of Bio-Engineering, Integral University, Lucknow, 226026, India. shazibiotech@gmail.com.
authors.forename: Shazi
authors.initials: S
authors.lastname: Shakil
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000928:Antidepressive Agents / Q000737:chemistry / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D003521:Cyclopropanes / Q000737:chemistry / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D000078764:Milnacipran; D062105:Molecular Docking Simulation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D050486:Serotonin Plasma Membrane Transport Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000078764:Milnacipran