Molecular Dynamic Simulations-Based Conformational Analysis and Binding Study of CP-225917 on Farnesyl Transferase Enzyme ^†

Abstract

CP-225917 was isolated from unidentified fungi and exhibits farnesyl transferase and squalene synthase inhibitory activity. In the present investigation, computational studies including docking, molecular dynamic simulations, protein ligand interaction fingerprints (PLIF) analysis and pharmacokinetic properties calculations were performed on the molecule. The crystallographic structure (pdb id 3E37) was used for the docking and MD simulation studies and it provided a docking score of −11.3 and FTase inhibitory activity of IC₅₀ = 6000 nM. Further, the conformational analysis studied the different conformations obtained from the MD simulations and PLIF analysis showed that the compound has significant interactions with Lys164, Tyr166, His201, ArgB202, HisB248, TyrB300, LysB356, TyrB361, HisB362 and ZnC1001 residues in the chain A and B of the FTase protein. However, the MD simulations revealed that the molecule has major interactions with the residues in the B chain of the FTase enzyme. The tyrosine residues TyrB300 and TyrB361 form surface and side-chain acceptor interactions and the TyrB361 residue has an interaction with the backbone acceptor and donor interactions. The histidine residues exhibited hydrogen bonding interactions and LysB356 has ionic interactions. The Zn metal showed ionic interaction with the ligand molecules for the activity. The Molecular Dynamics simulations of the complexes showed significant RMSD and RMSF values within the limit revealing that the complex is stabilized with these residues. These computational studies and the reported biological activities of the compound showed that this compound may be used as lead compounds to develop novel FTase inhibitors.