Abstract
Understanding what and how physico-chemical factors of a ligand configure conditions for ligand-receptor binding is a key to accurate assessment of toxic potencies of environmental pollutants. We investigated influences of the dipole-driven orientation and resulting directional configuration of ligands on receptor binding activities. Using physico-chemical properties calculated by ab initio density functional theory, directional reactivity factors (DRF) were devised as main indicators of toxic potencies, linking molecular ligand-receptor binding to in vitro responses. The directional reactive model was applied to predict variation of aryl hydrocarbon receptor-mediated toxic potencies among homologues of chrysene with structural modifications such as the numbers of constituent benzene rings, methylation and hydroxylation. Results of predictive models were consistent with empirical potencies determined by use of the H4IIE-luc transactivation bioassay. The experiment-free approach based on first principles provides an analytical framework for estimating molecular bioactivity in silico and complements conventional empirical approaches to studying molecular initiating events in adverse outcome pathways.
Highlights
Understanding what and how physico-chemical factors of a ligand configure conditions for ligandreceptor binding is a key to accurate assessment of toxic potencies of environmental pollutants
For modeling interactions between ligands and receptor proteins, we explored two hypotheses; (a) different binding activities of various ligands with the same kind of receptor (AhR in this study) would solely depend on the ligand’s physico-chemical properties and (b) different binding activities would be resulted from the interaction of ligands with common properties of the receptor
Considering larger molecular weights of receptor proteins than that of ligand molecule, charges on receptors can be assumed to be fixed in space and result in rotation of the ligand to make its dipole moment vector align along the line of force action, while the ligand moves toward the receptor. This process would determine the relative orientation of a ligand to “active binding” sites of the receptor. Another necessary condition to be considered for optimal reactions, resulting in ligand-receptor binding, is distribution of “frontier molecular orbitals (FMOs)” of a ligand, that is, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO)
Summary
Understanding what and how physico-chemical factors of a ligand configure conditions for ligandreceptor binding is a key to accurate assessment of toxic potencies of environmental pollutants. In the case of xenobiotics, this includes up-regulation of genes coding for enzymes, such as cytochrome P450 1A1 (CYP1A1), which transforms xenobiotics[1] This receptor-mediated, enzyme regulation depends on ligand-specific binding affinity and especially since it is the first initiation event, provides the basis of toxicology. Various receptors and signal transduction pathways are known, kinetics of how ligands interact with responsive receptors remains imperfect and is currently undergoing intensive r esearch[2,3] To understand such ligand-specific events involved in adverse outcome pathways (AOPs) or functioning of drugs, knowledge of affinities of binding to receptors is fundamental[4]. Quantitative structure–activity relationships (QSAR) is one accepted alternative, in silico predictive method based on linear free energy models (LFEM) and statistical correlations between structure-related physico-chemical properties of ligands in form of molecular descriptors (numerical quantities) and previously experimented bioactivity data. Recently, molecular docking models, based primarily on steric considerations, are being used to analytically estimate the binding affinity of ligands with r eceptors[16,17]
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