Exploring binding modes of the selected inhibitors to phosphodiesterase delta by all-atom molecular dynamics simulations and free energy calculations

It’s favorable to alter KRas mutation’s location to endomembrane by interfering the binding of PDEδ (the prenyl-binding protein phosphodiesterase delta) to KRas. In the present work, the binding of four inhibitors (Deltarasin, allyl analogue, pyrazolopyridazinone derivative, and Deltazinone 1) to PDEδ is investigated with all-atom Molecular Dynamic (MD) simulations. The binding free energy calculation results reveal that van der Waals (VDW) energy provides the major force for affinity binding. Moreover, the binding energy decomposition indicates that residues R61 and I129 provide important contributions to binding energies in all systems. The conserved hydrogen bonds play crucial roles in anchoring the inhibitors to the exact site for binding. The results for conformational analysis of PDEδ/free and PDEδ/inhibitors systems show that the structures are more stable after the inhibitors’ binding to the PDEδ. It is also found that the most unstable system among four complexes is PDEδ/pyrazolopyridazinone derivative system whose α3-helix formed by the residues P113-Q116 disappears. This study may provide valuable information for the design of high potency PDEδ inhibitors.

Communicated by Ramaswamy H. Sarma     

Investigation of ligand selectivity in CYP3A7 by molecular dynamics simulations

Cytochrome P450 (CYP) 3A7 plays a crucial role in the biotransformation of the metabolized endogenous and exogenous steroids. To compare the metabolic capabilities of CYP3A7–ligands complexes, three endogenous ligands were selected, namely dehydroepiandrosterone (DHEA), estrone, and estradiol. In this study, a three-dimensional model of CYP3A7 was constructed by homology modeling using the crystal structure of CYP3A4 as the template and refined by molecular dynamics simulation (MD). The docking method was adopted, combined with MD simulation and the molecular mechanics generalized born surface area method, to probe the ligand selectivity of CYP3A7. These results demonstrate that DHEA has the highest binding affinity, and the results of the binding free energy were in accordance with the experimental conclusion that estrone is better than estradiol. Moreover, several key residues responsible for substrate specificity were identified on the enzyme. Arg372 may be the most important residue due to the low interaction energies and the existence of hydrogen bond with DHEA throughout simulation. In addition, a cluster of Phe residues provides a hydrophobic environment to stabilize ligands. This study provides insights into the structural features of CYP3A7, which could contribute to further understanding of related protein structures and dynamics.     

Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free energy calculations

Focal adhesion kinase is an important target for the treatment of many kinds of cancers. Inhibitors of FAK are proposed to be the anticancer agents for multiple tumors. The interaction characteristic between FAK and its inhibitors is crucial to develop new inhibitors. In the present article, we used Molecular Dynamic (MD) simulation method to explore the characteristic of interaction between FAK and three inhibitors (PHM16, TAE226, and ligand3). The MD simulation results together with MM-GB/SA calculations show that the combinations are enthalpy-driven process. Cys502 and Asp564 are both essential residues due to the hydrogen bond interactions with inhibitors, which was in good agreement with experimental data. Glu500 can form a non-classical hydrogen bond with each inhibitor. Arg426 can form electrostatic interactions with PHM16 and ligand3, while weaker with TAE226. The electronic static potential was employed, and we found that the ortho-position methoxy of TAE226 has a weaker negative charge than the meta-position one in PHM16 or ligand3. Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563 Leu567, Ser568 are all crucial residues in hydrophobic interactions. The key residues in this work will be available for further inhibitor design of FAK and also give assistance to further research of cancer.     

2D-QSAR study,molecular docking,and molecular dynamics simulation studies of interaction mechanism between inhibitors and transforming growth factor-beta receptor I (ALK5)

Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R², and R²_ADJ, proved to be credible. The cross-validations for the models (q²_LOO = 0.571 and 0.629, respectively) showed their robustness, while the external validations (r²_test = 0.703 and 0.764, respectively) showed their predictive power. Besides, the predicted binding free energy results calculated by MM/GBSA method were in accordance with the experimental data, and the van der Waals energy term was the factor that had the most significant impact on ligand binding. What is more, several important residues were found to significantly affect the binding affinity. Finally, based on our analyses above, a proposed series of molecules were designed.