Molecular modeling and QSAR studies on K(ATP) channel openers of the benzopyran type

The present paper describes our molecular modeling and quantitative structure-activity relationships (QSARs) studies on K(ATP) channel openers (KCOs) of the benzopyran type. In the first part we performed molecular modeling investigations with seven benzopyrans, varied at the C3- and C4-positions, in order to understand which molecular features at these positions are essentially effecting the biological activity. The impact of C6-substitution on biological activity was studied in the second part via HANSCH analysis. For this purpose physicochemical properties (charge distributions, lowest unoccupied molecular orbital (LUMO) energies, desolvation energies, volumes and dipole moments) were calculated for a set of 50 C6-varied benzopyrans. A QSAR equation was developed showing a relationship between the vasodilator activity and the direction of the dipole vector of the ligands. The conclusion can be drawn that a direct interaction between the C6-substituents and the receptor structure is not of primary importance. However, the substitutents influence the orientation of the whole ligand approaching the binding site. An unfavorably oriented ligand cannot bind to the binding site, thus exhibiting weak activity.