A molecular modeling study on binding of drugs to calmodulin

Computer-graphical methods have been used to study the interaction between a series of drugs and calmodulin. Based on the X-ray crystallographic coordinates of the alpha-C atoms of calmodulin, a molecular model of the helical sequences was built. The model has been used to derive two possible binding sites for phenothiazines and one binding site for penfluridol. The principal binding forces occur through contacts between acidic amino acids of calmodulin and the protonated side-chain nitrogen of the drugs as well as between a basic amino acid and the electronegative substituents of the aromatic rings. Calculated interaction energies show a good correlation with experimental inhibition data.