Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ζ Inhibitors with Fragment-Merging Strategy

Abstract

Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein–ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37 from the second chemical series. Compound 37 showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biological consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.

Protein–ligand binding affinity prediction of cyclin‐dependent kinase‐2 inhibitors by dynamically averaged fragment molecular orbital‐based interaction energy

“…The fragment molecular orbital (FMO) method 1–4 is a powerful computational tool for structure‐based drug design (SBDD) 5–7 . Inter‐fragment interaction energy (IFIE) analysis 3 examines protein–ligand interactions with quantum (electronic) effects at reasonable computational costs.…”

“…The fragment molecular orbital (FMO) method [1][2][3][4] is a powerful computational tool for structure-based drug design (SBDD). [5][6][7] Inter-fragment interaction energy (IFIE) analysis 3 examines protein-ligand interactions with quantum (electronic) effects at reasonable computational costs. Furthermore, by means of pair interaction energy decomposition analysis (PIEDA), 4 the interaction energy, ΔE, is decomposed into four energy terms: electrostatic (ES), exchange repulsion (EX), dispersion (DI), and charge transfer with higher-order mixed terms (CT + mix), which offer detailed information regarding protein-ligand interactions.…”