title: The importance of CH/pi hydrogen bonds in rational drug design: An ab initio fragment molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase.
abstract: The interaction energy was calculated, by the ab initio FMO method, for complexes between LCK protein and four inhibitors (staurosporine, BMS compound 2, and our compounds 3 and 4). In every case a number of CH/pi hydrogen bonds have been disclosed in the so-called adenine pocket. In complexes of 2, 3, and 4, CH/pi and NH/pi hydrogen bonds have been observed in another pocket. In view of the above results, the aniline ring of 3 was replaced by 2,6-dimethyl aniline to increase the potency for LCK kinase. A 10-fold increase in the potency has been achieved for 4 over 3. We suggest that the concept of weak hydrogen bonds is useful in the rational design of drugs.
authors.affiliation: Kissei Pharmaceutical Company Ltd., Central Research Laboratory, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano-Pref 399-8304, Japan. tomonaga_ozawa@pharm.kissei.co.jp
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tsuji
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Ozawa
authors.forename: Chiaki
authors.initials: C
authors.lastname: Handa
authors.forename: Harunobu
authors.initials: H
authors.lastname: Mukaiyama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nishimura
authors.forename: Satoko
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okazaki
mesh_terms: D015195:Drug Design; D004583:Electrons; D006860:Hydrogen Bonding; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)