Background: Calmodulin (CaM) is a ubiquitous, calcium-binding protein that can bind
to and regulate a multitude of different protein targets, thereby affecting many different cellular
functions. Binding ofsmall, hydrophobic molecules alter its function, as in the case of Phenothiazine
(PTZ). PTZ isan organic compound with a history of use as an antihelminth and frequently
quoted as a classic example of a pharmaceutical lead structure.Its derivatives are currently used as
antipsychotic drugs. Triflouperazine (TFP) is a phenothiazine derivative and a dopamine antagonist,
with antiemetic and antipsychotic activities. TFP exerts its antipsychotic effect by blocking central
dopamine receptors, thereby preventing effects like delusions and hallucinations caused by an excess
of dopamine. This agent also functions as a calmodulin inhibitor, thereby leading to an elevation
of cytosolic calcium. We have attempted to screen the extent of CaM specificity towards different
classes of TFP and PTZ.
Methods: Molecular docking approach using the Lamarckian Genetic Algorithm was used to elucidate
the basis of structural similarity of TFP and PTZ with CaM. In total, 3000 compounds were
studied. All of the antagonists were taken from PubChem database on the basis of the structural
similarity of TFP and PTZ.
Results: The docking result of these molecules with CaM demonstrated favored binding energies in
the range of -11.50 kcal/mol to -4.51 kcal/mol, with 8 molecules showing hydrogen bonds with the
active site residue Met124. Compound 1 was found to be the best CaM inhibitor. The Drug like and
chemical toxicity was also predicted for this compound.
Conclusion: Computational docking is a feasible method to screen inhibitor compounds against a
biomolecule of interest.