title: Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitors.
abstract: 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.
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Trani
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Matteo
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Colin H
authors.initials: CH
authors.lastname: MacKinnon
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Brookfield
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Ewa I
authors.initials: EI
authors.lastname: Chudyk
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Bodkin
authors.affiliation: Discovery Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Discovery Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.affiliation: Discovery Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004790:Enzyme Induction; D007191:Indazoles / Q000737:chemistry; D007376:Interleukin-2 / Q000502:physiology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011725:Pyridines / Q000737:chemistry; D011789:Quantum Theory
chemical_list: D052160:Benzothiazoles; D007191:Indazoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase