title: Substituent Effects on Drug-Receptor H-bond Interactions: Correlations Useful for the Design of Kinase Inhibitors.
abstract: Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted N-methyl-3-(pyrimidin-4-ylamino)benzenesulfonamide inhibitors that display excellent potency and selectivity against a broad spectrum of protein kinases. Crystal structures of prototypical members bound to the ATP-binding site of TNNI3K reveal two anchoring hydrogen bond contacts: (1) from the hinge region amide N-H to the pyrimidine nitrogen and (2) from the sulfonamide N-H to the gatekeeper threonine. Evaluation of various para-substituted benzenesulfonamides defined a substituent effect on binding affinity resulting from modulation of the sulfonamide H-bond donor strength. An opposite electronic effect emerged for the hinge NH-pyrimidine H-bond interaction, which is further illuminated in the correlation of calculated H-bond acceptor strength and TNNI3K affinity for a variety of hinge binding heterocycles. These fundamental correlations on drug-receptor H-bond interactions may be generally useful tools for the optimization of potency and selectivity in the design of kinase inhibitors.
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lawhorn
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Philp
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Graves
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Holt
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Kallander
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases