Guide to Structure-Based Ligand Optimization

Knowledge of the macromolecule structure and its interactions with small-molecule ligands can provide useful information in the design and optimization of lead compounds with enhanced binding affinities as the examples in the previous sections of this chapter have illustrated. - s Structure-based ligand optimization requires two pieces of information. 

After atomic coordinates for the protein-ligand complex have been obtained, several steps are required to generate a computer model suitable for FEP calculations. 

Add missing residues. Many residues are often missing from a published crystallographic study. Especially at either the C- or N-terminus of the protein, there may be no or very low electron density as a result of the high 

Assign charges to amino add side chains. The active site residue protonation state is important and can have a significant effect on binding affinity. The protonation states of amino acid residues such as His, Lys, Glu, and Asp are usually based on their pX values but can be influenced by neighboring donor-acceptor groups. 

Develop force field parameters. Parameters may need to be developed for nonstandard residues as well as for the ligand and ions. The new parameters must be consistent and compatible with the rest of the force field. 

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