title: Design, synthesis, and computational studies of inhibitors of Bcl-XL.
abstract: One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.
authors.affiliation: Contribution from Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois 60064, USA. cheol-min.park@abbott.com
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oie
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Nimmer
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D051020:bcl-X Protein