Homology Modeling and Docking Study on Plasmodium Protein Farensyl Transferase: A Viable Target to Combat Malaria

The contemporary therapeutic demand is to develop a new antimalarial agent with a novel mode of action. Recently, the Plasmodium protein farensyltransferase (Pf-PFT) has been suggested as a viable target to develop new and alternative antimalarial agent. The present work describes the homology modeling of Pf-PFT and docking study to provide a structural basis for the design of new Pf-PFT inhibitors and antimalarial agents. Homology model of Pf-PFT was developed using X-ray structure of Rat-PFT. The sequence alignment was done using ClustalW. The homology model of Pf-PFT was generated using Modeller 9v7. The outliers were identified using PROCHECK and were minimized by energy minimization. The docking study of two potent Pf-PFT inhibitors (BMS-214662 and SCH66336) were performed using GOLD5.0.1 software. The Pf-PFT is a heterodimeric protein which consist of α and β chains. The sequences of target and template were aligned using ClustalW and refined manually. Twenty five models of Pf-PFT were developed and the model with least objective function was selected for validation with PROCHECK and WHATIF. The docking of BMS-214662 and SCH66336 at substrate binding site of Pf-PFT identified important ligand-receptor interactions. Both inhibitors coordinated with zinc cofactor and adopt the conformations sufficient to inhibit substrate-Pf-PFT binding. A 3D-conformation of Pf-PFT was developed and validated by standard protocol. The docking study highlighted the crucial amino acid residues involved in drug-receptor interactions. The Pf-PFT model may be useful to design and develop new Pf-PFT inhibitors and anti-malarial agents.