Introduction
3D PDB structures are a strong instrument for identifying key direct or water mediated protein-ligand interactions for a clear understanding of the bonding mode of compounds and support rational drug design efforts. They usually need to be carefully prepared to solve some issues (e.g. missing H atoms, alternate states, missing sidechains or loops, etc.). The MOETM,1 Protonate 3D and Protein Preparation tools add H atoms and identify issues and suggest actions to take, but the input of the user is still very important for taking the final decisions, like giving the correct orientation to a particular chemical groups in the ligand, or removing water molecules not important for ligand binding. Simple visual inspection is not always enough and additional analyses (e.g. inspection of the electron-density map) are required. Moreover, while some types of intermolecular interactions (e.g. classical H-bonds and evident π-stack interactions) are well parameterized in molecular mechanics force fields, others are more difficult to identify because they are non-classical intermolecular forces (e.g. cation-π, CH-π, halogen-π, carbonyl n-π*, etc.), but still play fundamental roles. This is why the use of quantum mechanics (QM) is desirable for a more accurate understanding of ligand-protein interactions. Applications of QM methods in medicinal chemistry have been reported, and the Pair Interaction Energy Decomposition Analysis in particular (PIEDA) within the framework of the Fragment Orbital Method (FMO) has shown to be a powerful tool.2,3 Tools within MOETM (e.g. 3D RISM solvent analysis, Energy Minimize with Optimal OH orientation) as well as the integration with other software (e.g. WinCoot4 for electron-density analysis or GAMESS5 for QM approaches) can give an important support.
References
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