title: 'Inductive' charges on atoms in proteins: comparative docking with the extended steroid benchmark set and discovery of a novel SHBG ligand.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Faculty of Medicine, University of British Columbia, 2733 Heather Street, Vancouver, British Columbia V5Z 3J5, Canada. artc@interchange.ubc.ca
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shi
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Li
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Magid
authors.initials: M
authors.lastname: Fallahi
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D004563:Electrochemistry; D004583:Electrons; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011506:Proteins / Q000737:chemistry*; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry*; D013256:Steroids / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D008024:Ligands; D011506:Proteins; D012738:Sex Hormone-Binding Globulin; D013256:Steroids