Computational studies of natural product compound (CP-225917) for lead identification

In this investigation, a computational analysis of CP-225,917 (a natural product compound isolated from unidentified fungi) on the farnesyl transferase (FTase) enzyme has been performed using docking, PLIF, and molecular dynamics (MD) simulations methodologies to understand its binding interactions. The crystallographic structure of the FTase used for the study was obtained from the Protein Data Bank (PDB id 3E37), and docking, MD simulations, MMPBSA, and PLIF analysis were performed with Autodock 4.2, AMBER 12, and MOE software, respectively. The results showed that the residues such as Lys164, Tyr166, His201, ArgB202, HisB248, TyrB300, LysB356, TyrB361, HisB362, and ZnC1001 have predominantly contributed to the interactions with the molecules through side chain (hydrogen bond acceptor and donor), backbone (hydrogen bond acceptor and donor), surface, and ionic interactions. The aromatic rings in TyrB300 and TyrB361 form surface interactions, and the side chains of all these residues show hydrogen bonding interactions with the molecule. The ionic interaction also formed between the molecules and the residues (LysB356 and Zn²⁺ metal). The MD simulations study revealed that the complex showed significant RMSD and RMSF values below 2.5 Å, confirming that the residues have stabilized the complex. The MM/PBSA analysis also confirms the significant binding affinity of the molecule with the protein. These computational studies concluded that the mode of interactions of CP-225,917 is similar to the other reported compounds on the target and will be a lead compound for the design and development of novel bioactive FTase inhibitors.

The online version contains supplementary material available at 10.1007/s40203-025-00405-6.