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.
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.
Ozawa
Tomonaga
T
Kissei Pharmaceutical Company Ltd., Central Research Laboratory, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano-Pref 399-8304, Japan. tomonaga_ozawa@pharm.kissei.co.jp
Tsuji
Eiichi
E
Ozawa
Motoyasu
M
Handa
Chiaki
C
Mukaiyama
Harunobu
H
Nishimura
Toshihiro
T
Kobayashi
Satoko
S
Okazaki
Kosuke
K
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
D047428:Protein Kinase Inhibitors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)