期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 24, 页码 10311-10318出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.10.041
关键词
CH/pi hydrogen bond; Weak hydrogen bond; An ab initio fragment molecular orbital method; Weak molecular interaction; Leukocyte-specific protein tyrosine (LCK) kinase; Rational drug design; Structure based drug design; Kinase inhibitor
资金
- Ministry of Education, Culture, Sports, Science, and Technology [RSS21]
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. (C) 2008 Elsevier Ltd. All rights reserved.
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