An Orbital-Overlap Complement to Ligand and Binding Site Electrostatic Potential Maps.

Area of Science:

• Computational Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Orbitals and orbital overlap are fundamental in chemistry but underutilized in medicinal chemistry for drug-target interactions.
• Existing methods like frontier orbital (Fukui) analysis and electrostatic potential maps offer valuable insights but have limitations.

Purpose of the Study:

• Introduce and validate the "orbital overlap distance" (D(r)) as a novel metric for analyzing molecular orbital interactions.
• Demonstrate the utility of D(r) in medicinal chemistry, particularly for understanding drug-target binding and predicting drug activity.

Main Methods:

• Developed the "orbital overlap distance" (D(r)) to quantify the overlap between a test orbital and a system's computed orbitals.
• Applied D(r) analysis to metal cation coordination chemistry and enzyme-ligand binding sites.
• Integrated D(r) with electrostatic potential mapping for a comprehensive analysis of binding interactions.

Main Results:

• D(r) effectively differentiates coordination chemistries of metal cations with similar charges and radii.
• Combined D(r) and electrostatic potential analysis elucidated "hard" versus "soft" cation binding in formylglycine-generating enzyme.
• Extended frontier orbital analysis using D(r) to quantify the behavior of promiscuous binders.

Conclusions:

• Orbital overlap distance is a valuable addition to medicinal chemistry, complementing electrostatic potential analysis.
• The combined approach offers a richer understanding of drug-target interactions and chemical binding.
• This method provides novel, experimentally testable predictions for optimizing drug efficacy, as demonstrated with centromere-associated protein E inhibitors.