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

Orbitals and orbital overlap are important concepts in chemistry but are seldom incorporated into medicinal chemistry analyses of drug-target interactions. Our orbital overlap distance D(r) quantifies the size of the "test orbital" that best overlaps with a system's computed orbitals at point r. The overlap distance provides information about all of the occupied orbitals across a molecule, extending frontier orbital (Fukui) analysis and complementing widely used maps of the surface electrostatic potential. We present the first tests of the overlap distance for problems in medicinal chemistry. The overlap distance quantifies the different coordination chemistries of pairs of metal cations possessing similar charges and ionic radii. Combining the overlap distance and electrostatic potential provides a rich picture of the binding sites for chemically "hard" versus "soft" cations in formylglycine-generating enzyme and extends frontier orbital analysis in quantifying the chemistry of promiscuous binders. We conclude by showing how the electrostatic potential and overlap distance combine to give a novel and experimentally testable prediction for improving the in vivo activity of centromere-associated protein E inhibitors. The results motivate including the overlap distance alongside electrostatic potential maps in medicinal chemistry.