Abstract
This review discusses current topics on the experimental and theoretical parameters of thermodynamics and drug design. Freire reported that change in the interaction enthalpy (ΔH) measured with isothermal titration calorimeter (ITC) could provide valuable information for drug design. Kitaura and his coworkers developed the fragment molecular orbital (FMO) method for quantum-chemical calculation of large molecules such as proteins. The FMO method has been applied to studies of whole protein and protein-ligand interactions. CH/π hydrogen bond is a weak interaction similarly to CH/O, OH/π, and NH/π. However, recent studies have elucidated that the CH/π hydrogen bond exists in many biomolecues and they play an important role in recognition between protein and ligand. Recently we calculated the interaction energies for complexes between LCK protein and three inhibitors (staurosporine 1, and our compounds 2 and 3) with the FMO method. In every case a number of CH/π hydrogen bonds have been disclosed in the binding pocket. In the compound 2, NH/π and CH/O hydrogen bonds have been observed as well. In order to increase the potency for LCK protein the aniline ring of the compound 2 was replaced with 2,6-dimethyl aniline in the compound 3. A ten-fold increase in the potency has been achieved for 3 over 2. We suggest that to pay attention to the weak hydrogen bonds is useful in the systematic drug design.
https://ror.org/028gkfr23 
