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Combinatorial Chemistry & High Throughput Screening
ISSN (Print): 1386-2073
ISSN (Online): 1875-5402
Epub Abstract Ahead of Print
DOI: 10.2174/1386207317666140120122920      Price:  $95

Theoretical Studies on Binding and Specificity Mechanisms of Farnesyltransferase (FTase) and Geranylgeranyl transferase type-I (GGTase-I) Inhibitors by Molecular Modeling

Author(s): Shirou Zhou
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Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) are two members of protein prenyltransferases, and they 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 simulation approaches were employed to study the bindings of two highly selective inhibitors (lonafarnib and GGTI-2133) towards FTase or GGTase-I. Molecular docking, molecular dynamics (MD) simulations and MM/GBSA free energy calculations were combined to predict the binding modes and evaluate the binding affinities of the studied inhibitors bound with GGTase-I and FTase. The specificities of the studied inhibitors derived from the predicted binding free energies are in good agreement with the experimental data. The analysis of the energetic components illustrates that both the non-polar and polar interactions play critical roles for 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
Department of Basic Medicine, Yueyang Vacational Technical College, Yueyang, Hunan 414000, China