In Silico molecular docking and molecular dynamic simulation of transferrin coated Phenytoin loaded SLNs with molecular targets of epilepsy

Abstract

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, affecting millions of people worldwide. Phenytoin is a widely used antiepileptic drug, but its therapeutic efficacy is limited by poor brain penetration and undesirable side effects. We have investigated the drug against the selected candidate's protein target using Insilco analysis to check the mode of action in real time system. This makes Phenytoin a promising therapeutic drug for the management of different targets involved in Epilepsy disease. Considering this, using a wide range of computer aided drug-designing approaches, high interactions with the protein targets have been inferred against drug molecule Phenytoin. Eight receptors against Phenytoin molecules showed binding interactions during molecular docking but the top four i.e. Bcl-2, BDNF, IL-1β and Caspase showed high binding affinities with docking score of 7.8 kcal/mol, 7.7. kcal/mol. 7.4 kcal/mol and 7.1 kcal/mol respectively. The compound Phenytoin interacts with several important active side residues in the active domain of all the receptors which was further validated via molecular dynamic simulations for 100 ns time intervals. Furthermore, the complexes of Phenytoin reveal very stable dynamics with average RMSD, RMSF and ROG values with stable carbon-alpha atoms confirmation at different intervals. In conclusion, these molecules are promising and require experimental validation to prove them as epilepsy inhibitors.

Fig 1. Flow chart of the current study depicting the steps used during the Insilco analysis.

Fig 2. Active Binding domains of Top complex for Epilepsy disease targets with clouds of hydrogen bonds acceptor and donor atoms. (A) depicts phenytoin in complex with Bcl2 (B) shows the phenytoin in complex with BDNF (C) shows phenytoin in complex with beta1 and (D) illustrate the phenytoin in complex with caspase target along the key interacting residues.

Fig 3. The top complexes regulate the binding shape and how the ligand molecule in complex with receptor interacts with them as shown here in this Fig. (A) BCL2 (2) BDNF (C) Beta-1 and (D) Caspase docked complex.

Fig 4. Transferin-receptor complex with binding residues involved in hydrogen and hydrophobic reactions.

Fig 5. Molecular dynamics simulations-based statistical analysis (RMSD) to evaluate the dynamics and intermolecular stability of the Epilepsy target protein in complex with Phenytoin compound for 100ns simulation time intervals.

Fig 6. Molecular dynamics simulations-based statistical analysis (RMSF) to evaluate the dynamics and intermolecular stability of the Epilepsy target protein in complex with Phenytoin compound for 100ns simulation time intervals.

Fig 7. Molecular dynamics simulations-based statistical analysis (RMSF) to evaluate the dynamics and intermolecular stability of the Epilepsy target protein in complex with receptor Transferrin for 100ns simulation time intervals.

Fig 8. Depicting Molecular dynamics simulations-based statistical analysis (RMSF) to evaluate the dynamics and intermolecular stability of the Epilepsy target protein in complex with receptor Transferrin for 100ns simulation time intervals.

Fig 9. (A) Trajectories analysis of Bcl-2 complex system with initial and final frame. (B) shows the Bdnf-complex system with initial and final frame trajectory (C) depicts the beta1-complex system with initial and final frame trajectory (D) illustrates the caspase-complex system with initial frame trajectory and (E) presenting the control complex system with initial frame trajectory.