Molecular docking studies on protein-ligand systems : application of current methodologies and development of (protein-specific polarized charge) PPC-based docking

The study of interaction of proteins to their binding small molecules has considerable practical importance in pharmaceutical industry and biomedical chemistry. Frequently, research in this arena is conducted by applying molecular docking computationally. This thesis presents molecular docking studies on protein-ligand systems in two parts: application of current methodologies (projects 1 - 3) and development of (protein-specific polarized charge) ppc-based docking (project 4). In the first study, molecular docking was utilized to computationally design and analyze of a novel series of norborane-based HIV-1 protease (PR) inhibitors with the goal of achieving more favorable binding orientations towards each binding site of PR. Our results demonstrated that the designed norborane inhibitor was not only able to mimic the hydrogen bonding features of the key structural water but contains the diol functionality as a transition state mimic to interact with the catalytic aspartates Asp25/Asp25’. This result created suggestions for successive design of more effective drugs against drug-resistant mutant of the virus. Second, docking of the known drug, raltegravir, to HIV-1 integrase (IN) based on the established Relaxed Complex Scheme (RCS) method, which accounts for the full flexibility of protein in docking, revealed two binding conformations of the drug with tighter binding involving the new binding trench, indicating that this technique would be useful for the design of future inhibitors. Third, molecular docking of the hit compound, scutellarin, to the peroxisome proliferator-activated receptors (PPARs) with the calculation of their binding free energy using molecular dynamics (MD) simulations suggested that scutellarin had comparable affinity to all three PPARs, but only able to form a believed critical hydrogen bond with PPARα, and thus could only activate PPARα. The binding mechanism of scutellarin discovered in this study would provide insights for developing it into a potential lead compound of drugs treating obesity. Finally, to achieve high accuracy in general docking, we included effect of protein polarization in molecular docking. We performed dockings on a diverse set of 100 protein-ligand complexes with the polarized protein-specific charge(s) (PPC), where QM/MM (quantum mechanical/molecular mechanical) force filed estimation of the partial charge of the protein residues was employed. Our result demonstrated that calculating the fully polarized residue charge was able to improve the docking accuracy for the test set proteins comparing to original electronegativity-based charges. This preliminary suggested for successive incorporation of the charge calculation algorithm into the general docking protocol to improve protein-ligand docking accuracy.Master of Scienc