PREDICTION OF STRUCTURES AND BINDING CONSTANTS OF DRUG-RECEPTOR COMPLEXES BY HYDROPHOBIC SURFACE AREAS

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1. We developed a computer software to calculate the decrease of molecular surface area with docking of host and gust and applied it to predict the structure and the binding constant of their complex. The structure in which this decreased area has the maximum is the most stable and the binding constant is uniquely correlated with this area, regardless of various host-guest systems. This finding allows us to predict the structure and binding constant from the chemical structures of host and guest.2. The structure of oxyphenonium bromide in water was estimated from the maximum hydrophilic surface area and the minimum hydrophobic surface area. This structure was in excellent agreement with the NMR structure, though the molecular mechanics structure was slightly different from it. This fact demonstrates that the molecular mechanics calculation does not account for the hydration energy and should include this energy estimated from molecular surface areas.3. We developed the NMR method for binding constant determination. The NMR chemical shift referred to external standard must be corrected for the change in volume magnetic susceptibility. This correction gave a correct binding constant. We proposed two internal standards for anionic compounds. Furthermore, the binding constants for multiple equilibrium systems have been determined and were analyzed on the basis of the structures of complexes.4. We have demonstrated that the suppression of bitterness and hemolysis of drug by cyclodextrin is predictable from observed surface tensions or electromotive forces, regardless of the kind and concentration of cyclodextrin. These observed values directly correspond to the concentration of free drug molecule in the cyclodextrin solution.5. The present results serve for predicting the structure and binding constant of complexes, such as drug-receptor and enzyme-substrate, from the chemical structures of host and guest and will enable a rapid design of new drug and new formulation.