title: Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design.
abstract: We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone.
authors.affiliation: Department of Medicinal Chemistry, Genzyme Corp., 153 Second Avenue, Waltham, Massachusetts 02451, United States. andrew.good@genzyme.com
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Jinyu
authors.initials: J
authors.lastname: Liu
authors.forename: Bradford
authors.initials: B
authors.lastname: Hirth
authors.forename: Gary
authors.initials: G
authors.lastname: Asmussen
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xiang
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Biemann
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bishop
authors.forename: Trisha
authors.initials: T
authors.lastname: Fremgen
authors.forename: Maria
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gladysheva
authors.forename: Annuradha
authors.initials: A
authors.lastname: Jain
authors.forename: Katherine
authors.initials: K
authors.lastname: Jancsics
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Andrew
authors.initials: A
authors.lastname: Papoulis
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.forename: J David
authors.initials: JD
authors.lastname: Stepp
authors.forename: Ronnie R
authors.initials: RR
authors.lastname: Wei
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1