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The Application of QM/MM Refinement in Protein-Ligand Complexes for Structure-Based Drug Design
Xue Li, University of Florida
Determining the structure of a small molecule (drug candidate or lead compound) to a biological receptor (protein implicated in disease) is a necessary step in this methodology. The dominant experimental approach used to achieve this goal is X-ray crystallography, while nuclear magnetic resonance (NMR) plays a lesser role. X-ray techniques provide astounding insights into the structure of protein-ligand complexes, but can be hampered by the resolution to which a crystal diffracts and the refinement process can be hampered by the lack of good potentials for novel small molecule compounds. An approach to improve structure quality in protein-ligand crystallography is presented by introducing the hybrid quantum mechanics and molecular mechanics (QM/MM) methods.
The QM/MM refinement leads to improvement of the local geometry with more accurate potential function for the ligand of interest taking into account interactions between protein and ligands. Benzamidine or benzamidine derivative is a good mimic for the guanidinium moiety of the arginine, which is a potential nonpeptide anatagonist of the receptors. The geometries of benzamidine show different preferences in free and bound states in terms of a single internal rotational angle about the bond connecting amidine and phenyl moieties. The force parameters of benzamidine are not accurate in the traditional refinement. The environment of the active site can alter torsional profiles dramatically. QM/MM refinement could provide preferred conformations for benzamidine with the best explanations of the density, while making reasonable contacts with different receptors. As the methodology develops and is further refined, the tool-box of structure based drug design will gain an important new method which will enable drug development for targets inaccessible to today’s mainstream drug discovery paradigm.
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