Abstract

A theoretical study was performed of the comparative binding affinities to fragment (82-93) of calmodulin (CaM) of trifluoperazine (TFP) and three derivatives, in which the methylene chain linking the phenothiazine ring and the piperazinium group was lengthened by addition of one to three methylenes. The backbone of the oligopeptide was held in the alpha-helical conformation. The computations were performed with the SIBFA procedures (sum of interactions between fragments computed ab initio), which use empirical formulas based on ab initio self-consistent field computations. The interaction energy is the sum of the intermolecular phenothiazine derivative-oligopeptide interaction energy and of the separate intramolecular energy variations of the ligand, on the one hand, and of the oligopeptide, on the other hand, upon relaxing the conformations of side chains Glu 84, Glu 87, Phe 89 and Phe 92 due to complex formation. All three derivatives were found to display a higher binding affinity than did TFP itself, an optimal affinity being found for a four- and a five-methylene linker chain. In as much as fragment (82-93) of CaM is a plausible candidate receptor site for phenothiazines, these results imply that two such compounds should be endowed with a significantly greater anti-CaM activity than TFP itself.