title: Reassessment of Hammett σ as an effective parameter representing intermolecular interaction energy-links between traditional and modern QSAR approaches.
abstract: The Hammett σ constant has for a long time been known to be one of most important linear free-energy related parameters that correlate with biological activity. It is a conventionally used electronic parameter in studies of enzymatic quantitative structure-activity relationships (QSAR). However, it is not necessarily obvious why σ represents variations in the free-energy change associated with the complex formation between a congeneric series of ligands with their target protein. So far, several powerful molecular calculations, such as the ab initio fragment molecular orbital (FMO) one, that are directly applicable to ligand-protein complexes have emerged. In this study, we comprehensively reevaluate experimentally derived parameter σ confirming it represents intermolecular interaction energy terms, by applying molecular orbital (MO) calculations to a simple ligand-protein complex model. The current results provide a rational and quantitative basis for bridging the gap between the traditional QSAR approach and 'the modern QSAR one', which involves the molecular calculations to evaluate the overall free-energy change for complex formation.
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.forename: Miho
authors.initials: M
authors.lastname: Shimizu
authors.forename: Masataka
authors.initials: M
authors.lastname: Harada
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D000465:Algorithms; D001703:Biophysics / Q000379:methods; D002621:Chemistry / Q000379:methods*; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D000098:Acetophenones; D008024:Ligands; D011506:Proteins; C038699:acetophenone