In silico binding affinity study of calcineurin inhibitors to calcineurin and its close associates

Abstract

Calcineurin (CN) is a calcium regulated serine/threonine protein phosphatase. It is known to be inhibited by cyclosporin A (CsA), tacrolimus (FK506), endothall (ENDO), microcystin (MCYST), okadaic acid (OA) and trifluoperazine (TFP). CsA and FK506 are known inhibitors, which inhibit CN by binding to cyclophilin A (CyPA) and FK506 binding protein 12 (FKBP12), to form CsA-CyPA and FKBP12-FK506 complexes, respectively. These complex molecules finally bind to CN to inhibit its phosphatase activity. The mode of action of the inhibitors and their binding affinity to CN's subunits and close associates is not very clear. The current study is to dock CN subunits, such as, calcineurin A (CNA), calcineurin B (CNB) and calcineurin AB (CNAB), with known inhibitors as well as close associates of CN like calmodulin (CaM), FKBP12 and CyPA. This was done using Autodock Vina to evaluate their binding free energy (DG) and binding affinities. The results suggest that inhibition can be brought about by either directly binding to CN and its subunits or associates. The binding affinity of known inhibitors of CN is given as follows: OA>TFP>MCYST>FK506>CsA>ENDO. These inhibitors exhibit very low docked free energy not only with associates of CN, but also with CN subunits. These binding free energies suggest that inhibitors of CN and its associates have different binding affinities and also could exhibit complex inhibition rather than a direct inhibition of CN through a single mechanism