Binding mode analysis of chaetomallic acids (A and B) as farnesyltransferase inhibitors

Farnesyltransferase (FTase) is a major target in the development of potential anticancer drugs. In the present investigation, we have predicted the binding mode of natural product compounds chaetomallic acid A and B on the FTase enzyme. The docking, molecular dynamics simulations, protein ligand interaction fingerprint (PLIF) and in silico ADME prediction on these compounds were performed to analyse the binding mode interactions. The crystallographic structure (pdb id 3E33) was used for the docking and MD simulation studies and it provided the docking score of -8.5 and -7.55 for chaetomellic acid A and B respectively. The chain B of the FTase has significant interactions with these compounds. The results showed that some important residues, such as LeuB96, ArgB202, TyrB300, AspB359, TyrB361 and His362 are predominantly present in the complexes for interactions. In all protein-ligand complexes, the LeuB96 interacts with chaetomallic acid via surface interaction (solvent exposed surface). The Molecular Dynamics simulations of the complexes showed significant RMSD and RMSF values on stabilized complexes through interaction with TYR361, His362, Lys356, etc residues. In silico pharmacokinetic prediction of the compounds revealed that these compounds have high logP values (>5.5). It showed that these compounds are not metabolized by the CYP enzymes any hERG blocking activity. These compounds have reported FTse inhibitory activities of 55 nM and 185 nM for Chaetomellic acid A and B respectively. The binding interaction studies, in silico pharmacokinetic prediction and the reported biological activities of the compounds showed that it may be taken as lead compounds to develop novel FTase inhibitors.