title: Prediction of a new surface binding pocket and evaluation of inhibitors against huntingtin interacting protein 14: an insight using docking studies.
abstract: Protein-protein interactions play an important role in regulating the expression of huntingtin protein (htt). Expansion of polyglutamine tracts in htt results in neurodegenerative Huntington disease. Huntingtin interacting protein (HIP14) is an important interacting partner of htt and the altered interactions have been proposed to play an important role in disease progression. In the present study, an attempt has been made to explore the potential of several known Huntington inhibitors to inhibit HIP14. The docking studies have resulted in the identification of a novel binding site for these inhibitors distinct from the previously known ankyrin repeat domain. The results have been validated using geometry based docking transformations against the other binding pocket. The specificity of binding has been determined with high values of both accuracy and precision. Nine potential inhibitors obtained after screening belong to three distinct classes of compounds viz, carbohydrates (deoxy-glucose), alcohols (including phenolic scaffold) and tetracycline. The compounds form stable complex with protein exhibiting optimal intermolecular and Gibbs free energy. The hydrogen bonding and hydrophobic interactions predominantly contribute to the stability of these complexes. The present study identifies metoprolol, minocyclines and 18 F fluorodeoxyglucose as the best inhibitors that bind specifically to the new site. Therefore, these compounds can further be exploited for their potential to serve in the diagnosis and treatment of Huntington disease. The quantitative predictions provide a scope for experimental testing in future.
authors.affiliation: Biotech Park, Sector-G Jankipuram, Lucknow, 226021 Uttar Pradesh, India. shiprabioinfo@gmail.com
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.forename: Gauri
authors.initials: G
authors.lastname: Misra
authors.forename: Mohan C
authors.initials: MC
authors.lastname: Pant
authors.forename: Prahlad Kishor
authors.initials: PK
authors.lastname: Seth
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D008790:Metoprolol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008911:Minocycline / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013752:Tetracycline / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D019788:Fluorodeoxyglucose F18; C097188:polyglutamine; D000217:Acyltransferases; C473038:ZDHHC17 protein, human; D013752:Tetracycline; D008911:Minocycline; D008790:Metoprolol