Substituent Effects on Drug–Receptor H-bond Interactions: Correlations Useful for the Design of Kinase Inhibitors

摘要: Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment heart failure has produced series substituted N-methyl-3-(pyrimidin-4-ylamino)benzenesulfonamide inhibitors that display excellent potency and selectivity against broad spectrum protein kinases. Crystal structures prototypical members bound to ATP-binding site TNNI3K reveal two anchoring hydrogen bond contacts: (1) from hinge region amide N–H pyrimidine nitrogen (2) sulfonamide gatekeeper threonine. Evaluation various para-substituted benzenesulfonamides defined substituent effect on binding affinity resulting modulation H-bond donor strength. An opposite electronic emerged NH-pyrimidine interaction, which is further illuminated in correlation calculated acceptor strength variety heterocycles. These fundamental correlations drug–receptor H...