Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin‑2 Inducible T‑Cell Kinase (ITK) Inhibitors

Inhibition
of inducible T-cell kinase (ITK), a nonreceptor tyrosine
kinase, may represent a novel treatment for allergic asthma. In our
previous reports, we described the discovery of sulfonylpyridine (SAP),
benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI)
series as novel ITK inhibitors and how computational tools such as
dihedral scans and docking were used to support this process. X-ray
crystallography and modeling were applied to provide essential insight
into ITK–ligand interactions. However, “visual inspection”
traditionally used for the rationalization of protein–ligand
affinity cannot always explain the full complexity of the molecular
interactions. The fragment molecular orbital (FMO) quantum-mechanical
(QM) method provides a complete list of the interactions formed between
the ligand and protein that are often omitted from traditional structure-based
descriptions. FMO methodology was successfully used as part of a rational
structure-based drug design effort to improve the ITK potency of high-throughput
screening hits, ultimately delivering ligands with potency in the
subnanomolar range.