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

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• 作者：Alexander Heifetz ; Giancarlo Trani ; Matteo Aldeghi ; Colin H. MacKinnon ; Paul A. McEwan ; Frederick A. Brookfield ; Ewa I. Chudyk ; Mike Bodkin ; Zhonghua Pei ; Jason D. Burch ; Daniel F. Ortwine
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：59
• 期：9
• 页码：4352-4363
• 全文大小：917K
• 年卷期：0
• ISSN：1520-4804

文摘

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.