title: In silico evaluation of human small heat shock protein HSP27: homology modeling, mutation analyses and docking studies.
abstract: Small heat-shock proteins, possessing chaperone-like activity, represented crucial proteins actively involved in maintain protein homeostasis, which act to prevent improper polypeptide aggregation and deposition of misfolded proteins. In this context, a number of mutations concerning the HspB1 protein proved to be associated with the development of several neuropathologies. Unfortunately, molecular mechanisms underlying the onset of these diseases and in particular the changes induced by the mutations in HspB1 structure, remain poorly characterized. On the other hand, more recent studies demonstrated that HspB1 overexpression leads to an overactive chaperone activity, which in turn contributes to the anticancer agent resistance. On these basis, Hsp27 could represent a good innovative target for development of novel cancer therapy. Therefore, in this work a computational study, based on the homology model of the complete Hsp27 protein and of several pathological mutant forms, was developed. Finally, the derived model was employed to perform, for the first time, docking simulations on a recently identified Hsp27 inhibitor, disclosing a new useful panorama to be exploited for the further development of new compounds.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV n.3, 16132 Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV n.3, 16132 Genova, Italy. Electronic address: cichero@unige.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D015870:Gene Expression; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006360:Heat-Shock Proteins; D006801:Humans; D006860:Hydrogen Bonding; D018832:Molecular Chaperones; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D054852:Small Molecule Libraries / Q000737:chemistry*; D055672:Static Electricity; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D054852:Small Molecule Libraries
keywords: Docking; HSP27 inhibitors; HSPB1; Heat-shock proteins; Homology modeling