Guiding Medicinal Chemistry with Fragment Molecular Orbital (FMO) Method

• Published in: Methods in molecular biology (Clifton, N.J.) Vol. 2114; p. 37
• Main Authors: Heifetz, Alexander, James, Tim, Southey, Michelle, Bodkin, Mike J, Bromidge, Steven
• Format: Journal Article
• Language: English
• Published: United States 01.01.2020
• Subjects: Asthma - drug therapy; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Chemistry, Pharmaceutical - methods; Drug Design; Drug Discovery - methods; Humans; Quantum Theory; IND indazole ITK inhibitors; Benzothiazole ITK inhibitors; FMO fragment molecular orbitals method; SAR; ITK interleukin-2 inducible T-cell kinase; PIE pair interaction energy; BZT; PIEDA pair interaction energy decomposition analysis
• ISSN: 1940-6029
• DOI: 10.1007/978-1-0716-0282-9_3

The understanding of binding interactions between a protein and a small molecule plays a key role in the rationalization of potency and selectivity and in design of new ideas. However, even when a target of interest is structurally enabled, visual inspection and force field-based molecular mechanics calculations cannot always explain the full complexity of the molecular interactions that are critical in drug design. Quantum mechanical methods have the potential to address this shortcoming, but traditionally, computational expense has made the application of these calculations impractical. The fragment molecular orbital (FMO) method offers a solution that combines accuracy, speed, and the ability to characterize important interactions (i.e. its strength in kcal/mol and chemical nature: hydrophobic, electrostatic, etc) that would otherwise be hard to detect. In this chapter, we describe the FMO method and illustrate its application in the discovery of the benzothiazole (BZT) series as novel tyrosine kinase ITK inhibitors for treatment of allergic asthma.