In silico discovery of novel calcineurin inhibitors using ligand-based 3-D pharmacophore modelling and molecular dynamics simulation

Calcineurin is a serine-threonine protein phosphatase that is activated with the binding of calmodulin in the presence of increased calcium concentration and has a major role in various signaling pathways. Its role in regulating homeostasis, developmental processes, and different disease progression has already been reported. The dysregulated Ca2+/calcineurin/NFAT1-4 pathway is observed in Autoimmune disorders and hence the use of Calcineurin inhibitors like Cyclosporin A (CsA) and Tacrolimus (FK506) is widely done in such cases. Recent studies indicate the uncontrolled overexpression of the Calcineurin protein in the pathophysiological pathway of neurodegenerative diseases. The in vitro and animal model studies with standard calcineurin inhibitors (CnIs), which are widely labeled as immunosuppressant drugs, have shown a significant reduction of neurodegeneration in respective models. These results compel the identification of novel calcineurin inhibitors against neurodegenerative diseases. With this scenario, the present work focuses on the computer-aided identification of novel CnIs via ligand-based 3-D pharmacophore modelling. Known CnIs, CsA, and FK506, were used to build the pharmacophore models which were validated and screened against external databases to retrieve possible hits. Docking investigations, pharmacokinetic properties, and molecular dynamics simulations along with toxicity predictions were performed on the hits that were obtained. According to the study, a total of 5 molecules ILB 162, ILB 005, ILB 439, ILB 390, and ILB 198, were found to be the best calcineurin inhibitors with binding affinity in the range of -9.7 to -9.0 Kcal/mol with 1MF8 (PDB). The stability of interactions of these molecules was further validated via Molecular dynamics simulation studies to confirm these to be the potential calcineurin-inhibiting molecules.