title: In silico identification of potential dynamin-related protein 1 antagonists: implications for diseases involving mitochondrial dysfunction.
abstract: Mitochondria are the center of metabolism and the critical role of aberrant mitochondrial fission in the onset and progression of a wide range of human diseases such as neurodegenerative disorders, cardiovascular disease, ischemic stroke and diabetes, is slowly becoming recognized. Under physiological conditions, mitochondrial structure is predominantly regulated by cycles of fusion and fission, which is very crucial for the maintenance of cellular homeostasis. Dynamin-related protein 1 is a GTPase that catalyzes the process of mitochondrial fission and is also associated with the excessive fragmentation of mitochondria, impaired mitochondrial dynamics and cell death. Hence, identification of potent and selective antagonists is prerequisite to successfully exploit the therapeutic effects of Drp1 inhibition. In this study, an integrated in silico strategy that includes homology modeling, pharmacophoric, docking analysis and molecular dynamics simulations was employed in designing the potential Drp1 inhibitors. A homology model of Drp1 was generated employing crystal structure of dynamin protein as a template. Pharmacophoric features were developed for the GTPase domain of dynamin-related protein 1 and were used to screen ZINC-database. The obtained hits were docked to the same domain. The binding mode analysis of these ligands showed all the essential binding interactions required in the inhibition of Drp1. Furthermore, explicit solvent simulations were carried out using the two most potential hits to validate the docking analysis and to study the overall stability of the binding site interactions. The present study not only provides a structural model of Drp1 for rational design of apoptotic inhibitors, but also identifies six potential compounds for further development.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Hanumanthappa
authors.affiliation: School of Biotechnology, Coordinator, DBT - Bioinformatics Center, National Institute of Technology Calicut, Calicut - 673601, India. rajanikant@nitc.ac.in.
authors.forename: Golgodu K
authors.initials: GK
authors.lastname: Rajanikant
mesh_terms: D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000188:drug therapy; D018360:Crystallography, X-Ray; D062126:Databases, Chemical; D055808:Drug Discovery; D034281:Dynamins; D004791:Enzyme Inhibitors / Q000737:chemistry*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins