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

Theoretical Studies on Binding and Specificity Mechanisms of Farnesyltransferase (FTase) and Geranylgeranyl transferase type-I (GGTase-I) Inhibitors by Molecular Modeling. Comb Chem High Throughput Screen. 2014 Jan 20; Authors: Zhou S Abstract 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,...
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research