title: Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities.
abstract: The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated antiproliferative activity at ∼150 nM concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.
authors.affiliation: Istituto di chimica del riconoscimento molecolare, CNR. Via Mario Bianco 9, 20131 Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D017076:Computer-Aided Design; D055808:Drug Discovery / Q000379:methods* / Q000706:statistics & numerical data; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009675:Novobiocin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D009675:Novobiocin