‘Inductive' Charges on Atoms in Proteins: Comparative Docking with the Extended Steroid Benchmark Set and Discovery of a Novel SHBG Ligand

We have developed a novel iterative approach for calculation of partial charges in proteins within the
framework of the ‘molecular capacitance' model. The method operates by an effective ‘inductive'
electronegativity scale derived from a number of the conventional charge systems including CHARMM,
AMBER, MMFF, OPLS, and PEOE among others. Our novel ‘inductive' electronegativity equalization
procedure allows rapid and conformation sensitive computation of adequate partial charges in proteins.
Accuracy of the ‘inductive' values was confirmed by their correlation with DFT-computed partial charges
in common amino acids. A comparative docking study with an extended steroid data set not only illustrated
the adequacy of ‘inductive' protein charges but also demonstrated their superior performance compared to
several conventional protein charging systems. Subsequent docking with ‘inductive' charges resulted in
identification of five potential leads as human Sex Hormone Binding Globulin (SHBG) ligands from a
commercial library of natural compounds. When the selected substances were evaluated for their ability to
bind SHBG in vitro, three of them displaced testosterone from the SHBG steroid-binding site, and with one
compound this was achieved at micromolar concentrations.