Molecular Design And Modeling Study Of Two Important Protein Inhibitors

With the development of computational technology, bioinformatics and other interdisciplinary, molecular modeling as a newly technique of drug development has been applied to study the discovery of potential drug targets and the mechanisms of protein-ligand interactions. Based on the structure of protein and inhibitors, the molecular modeling techniques (3D-QSAR, molecular docking, molecular dynamic simulation and binding free energy calculation) were used to explore molecular structure features to their bioactivity and study the interaction mode between the targeted protein and their inhibitors, which aids the design and synthesis of highly effective inhibitors.In Chapter1, we present a general introduction of the computer-aid drug design method, such as3D-QSAR, molecular docking, molecular dynamic simulation and binding free energy calculation. We also describe and overview the recent progress in the study of protein and protein inhibitors. Finally, the work of this paper was summed briefly.In chapter2, a multistep framework combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations was performed to explore structural features affecting the activities of BACE-1inhibitors and study the molecular mechanism of receptor-ligand interactions. The proteolytic enzyme β-secretase (BACE-1) is one of potential drug targets for treating Alzheimers’s disease.3D-QSAR models of BACE-1inhibitors were developed from the conformations obtained by molecular alignment and several important structural factors that mainly influence the inhibitory activity were obtained. Then, molecular dynamics simulations including binding free energy calculations and per-residue energy decomposition revealed that the binding free energies had the higher correlational relationship with the experimental activity values. The van der Waals and electrostatic interactions were the major driving force for the binding of compounds to BACE-1. Finally, several derivatives were designed and validated by molecular modeling. Our studies were beneficial to give theoretical guidances of the development of potent and highly active inhibitors of BACE-1.In chapter3, the interactions between a series of pyrido[2,3-d]pyrimidine inhibitors and DYRK1A were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations and binding energy decomposition analysis. DYRK1A is a promising target for a number of diseases including Down syndrome, oncological disease and Alzheimers’s disease. First, three docking protocols including rigid receptor docking, induced fit docking and QM-polarized ligand docking were used to predict the binding modes of the studied inhibitors in the active site of DYRK1A. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes between the inhibitors with different activities and DYRK1A. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. Finally, we also conducted a detailed analysis of inhibitors with different groups binding to DYRK1A in comparison with molecule14, which was exploited for gaining structural features of potential and highly selective DYRK1A inhibitors. Based on these results of DYRK1A-inhibitor interactions, some derivatives were designed and the higher inhibitory activities of several candidates were conformed by molecular docking.