title: Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8.
abstract: Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand-receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT.
authors.affiliation: Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan; State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China; University of Chinese Academy of Sciences, Beijing, People's Republic of China; Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan.
authors.forename: Sheikh Arslan
authors.initials: SA
authors.lastname: Sehgal
authors.affiliation: Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan.
authors.forename: Shazia
authors.initials: S
authors.lastname: Mannan
authors.affiliation: Department of Bioscience, COMSATS Institute of Information Technology, Sahiwal, Pakistan.
authors.forename: Sannia
authors.initials: S
authors.lastname: Ali
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011485:Protein Binding; D014584:User-Computer Interface
chemical_list: D000928:Antidepressive Agents; D006360:Heat-Shock Proteins; D008024:Ligands
keywords: HSPB8; antidepressants; bioinformatics; computer-aided drug design; heat shock protein (HSP); modeling; molecular docking; neurodegenerative disorders; pharmacoinformatics; virtual screening