In Silico Prediction of Interactions between Site II on Human Serum Albumin and Profen Drugs

Since binding of a drug molecule to human serum albumin (HSA) significantly affects the pharmacokinetics of the drug, it is highly desirable to predict the binding affinity of the drug. Profen drugs are a widely used class of nonsteroidal anti-inflammatory drugs and it has been reported that several members of the profen class specifically bind to one of the main binding sites named site II. The actual binding mode of only ibuprofen has been directly confirmed by X-ray crystallography. Therefore, it is of interest whether other profen drugs are site II binders. Docking simulations using multiple template structures of HSA from three crystal structures of complexes between drugs and HSA have demonstrated that most of the currently available profen drugs should be site II binders. 1. Introduction Human serum albumin (HSA) which is the most abundant plasma protein binds vast array of chemically diverse exogenous and endogenous molecules [1]. Binding of a drug molecule to HSA results in increased solubility in plasma, decreased toxicity, and protection against oxidation of the bound molecule. Since HSA binding is one of the important factors which determine the ADME properties of the drugs, it is highly desirable to know the binding affinity of drugs in order to avoid undesirable drug-drug interactions. There are two approaches to predict protein-ligand interactions. Ligand-based approaches mostly use quantitative structure-activity relationships (QSARs) which are based on chemical structures and physicochemical properties of a series of compounds whose HSA binding affinities have been measured [2]. High-resolution crystal structures of HSA complexed with various molecules have shown that there are two main binding sites named sites I and II [3]. As site I is large and flexible multichamber, a variety of different molecules can bind to site I. On the contrary, ligands binding to site II are usually aromatic carboxylic acids with a negative charged group at one end of the molecule away from a hydrophobic center. Based on the reliable crystal structures, structure-based approaches are possible. The molecular docking methods, in particular, which have been largely improved recently can be applied to predict the interaction modes of drugs and the binding sites in atomic detail comparable to the experimental results. Since nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications [4], the drug-drug interactions involving NSAIDs are important issues in many drug discovery projects. In particular, 2-aryl propionic acids (profen