Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) are two members of protein
prenyltransferases, which play critical roles in lipid post-translational modifications. Potent inhibitors of FTase and
GGTase-I have been confirmed to show favorable influence on the therapies of various diseases, such as cancers, malaria
and Toxoplasmosis. However, designing highly specific inhibitors toward FTase or GGTase-I without influencing their
binding affinity remains a big challenge. In this work, molecular docking, molecular dynamics (MD) simulations and
MM/GBSA free energy calculations were employed to study the bindings of two highly selective inhibitors (lonafarnib
and GGTI-2133) towards FTase or GGTase-I. The specificities of the studied inhibitors derived from the predicted
binding free energies are consistent with the experimental data. The analysis of the energetic components illustrates that
both the non-polar and polar interactions play critical roles in determining the specificity between FTase and GGTase-I.
Moreover, the protein-inhibitor interaction spectra for the studied inhibitors were determined through the decomposition
of the binding free energies, and the important residues for binding and specificity were highlighted. Our study provides
useful information for the rational design of selective FTase or GGTase-I inhibitors.
Keywords: Free energy decomposition, FTase, GGTase-I, MM/GBSA, molecular docking, molecular dynamics simulations,
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