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Bioorg Med Chem. 2008 Dec 15;16(24):10311-8. doi: 10.1016/j.bmc.2008.10.041. Epub 2008 Oct 22.

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.

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Kissei Pharmaceutical Company Ltd., Central Research Laboratory, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano-Pref 399-8304, Japan.


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.

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