Electrostatic complementarity between proteins and ligands. 2. Ligand moieties

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Drug design often employs fragment-based strategies, sequentially building ligands within a receptor site.
• Optimization is typically performed on individual fragments during this process.

Purpose of the Study:

• To investigate whether sequential fragment optimization in drug design yields optimal electrostatic interactions.
• To determine if whole-ligand electrostatic complementarity can be predicted from individual fragment complementarities.

Main Methods:

• Calculation of electrostatic complementarities between ligand fragments (moieties) and the receptor site.
• Comparison of whole-ligand complementarity with the sum or average of individual moiety complementarities.

Main Results:

• Whole-ligand electrostatic complementarity is not the simple mathematical mean of individual moiety complementarities.
• No straightforward relationship was found between moiety and whole-ligand electrostatic complementarities.
• Predicting whole-ligand electrostatic complementarity from constituent parts using simple models is challenging.

Conclusions:

• Current fragment-based drug design optimization strategies may not achieve optimal electrostatic interactions.
• Drug design requires a global optimization approach for electrostatic complementarity, not a moiety-by-moiety method.