A molecular modeling study on binding of drugs to calmodulin

SummaryComputer-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 α-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.

[1]  R J Beynon,et al.  Prevention of unwanted proteolysis. , 1988, Methods in molecular biology.

[2]  J. Gasteiger,et al.  ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES , 1980 .

[3]  Bernard Pullman,et al.  Quantum-Mechanical Approach to the Conformational Basis of Molecular Pharmacology , 1977 .

[4]  R J Williams,et al.  The nature of the trifluoperazine binding sites on calmodulin and troponin-C. , 1984, Biochimica et biophysica acta.

[5]  B. E. Robertson,et al.  Purification, growth, structure, optical and electrical properties of single crystals of the π‐molecular complex of phenothiazine with pyromellitic dianhydride , 1980 .

[6]  Charles E. Bugg,et al.  Three-dimensional structure of calmodulin , 1985, Nature.

[7]  D. Puett,et al.  Binding of trifluoperazine and fluorene-containing compounds to calmodulin and adducts. , 1986, Biochemical pharmacology.

[8]  B. Weiss,et al.  Mechanism by which psychotropic drugs inhibit adenosine cyclic 3',5'-monophosphate phosphodiesterase of brain. , 1976, Molecular pharmacology.

[9]  E Carafoli,et al.  Influence of Ca2+ and trifluoperazine on the structure of calmodulin. A 1H-nuclear magnetic resonance study. , 2005, European journal of biochemistry.

[10]  Wai Yiu ed. Cheung,et al.  Calcium and cell function , 1980 .

[11]  E Carafoli,et al.  Calmodulin-drug interaction. A fluorescence and flow dialysis study. , 1987, Cell calcium.

[12]  M. James,et al.  Two trifluoperazine‐binding sites on calmodulin predicted from comparative molecular modeling with troponin‐C , 1988, Proteins.

[13]  B. Weiss,et al.  Inhibition of calmodulin by phenothiazines and related drugs: structure-activity relationships. , 1982, The Journal of pharmacology and experimental therapeutics.

[14]  B Pullman,et al.  A theoretical study of the binding of phenothiazine derivatives to residues 82-93 of calmodulin. , 1986, Molecular pharmacology.

[15]  R E Reid,et al.  Drug interaction with calmodulin: the binding site. , 1983, Journal of theoretical biology.

[16]  J Gariépy,et al.  Localization of a trifluoperazine binding site on troponin C. , 1983, Biochemistry.

[17]  B. Weiss,et al.  Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. , 1979, The Journal of pharmacology and experimental therapeutics.

[18]  J. J. H. McDowell,et al.  The crystal and molecular structure of chlorpromazine , 1969 .

[19]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.