Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors

Conclusion An integrating computational case study, which involves molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations and decompositions, has been conducted toward type I1/2 NIK inhibitors to further illuminate their binding mechanisms. As conventional RRD docking methods and IFD cannot well reflect the relative activity, ensemble docking by using MRCs is adopted and the docking result is largely improved, suggesting that protein flexibility is vitally important in type I1/2 inhibitors binding. Then, MD simulations combined with MM/GB(PB)SA binding free energy calculations are used to further explore NIK-ligand interactions. It is found that a remarkably improved linear correlation can be observed between prediction and experimental activities, implying that MM/GB(PB)SA is adaptable for the prediction of the binding of NIK and its inhibitors. Further analysis shows that hydrophobic interactions play the most essential role in ligand binding, whereas the polar contributions consisting of the electrostatic interactions and the polar contribution of solvation effect, also take some effect. Next, H-bond analysis as well as MM/GBSA decomposition is carried out and several key residues are specially revealed. A deeper comparison of several pairs of representative inhibitor derivatives illustrates that the activity difference of a series of analogs also greatly depends on the non-polar contributions. Likewise, the H-bond interactions wi...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research