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     ...Introduction to Protein Binding

Definition of Protein Binding Activity Data

Protein binding values (% fraction bound) are normally given as the percentage of the total plasma concentration of a drug that is bound to all plasma proteins. 

In most cases, binding to plasma proteins is reversible, and the concentration of the free and bound species of the drug at equlibrium may be expressed as:

The total plasma concentration of the drug is expressed as the sum of the percent of free drug and the percent bound.

Binding measurements are made in vitro, at multiple drug plasma concentration levels in the clinically achievable range.   A single (average) value result of such measurements indicates a relatively constant bound-to-free ratio over the range of plasma concentrations examined.  In situations where drug binding is concentration dependent, two values are given, representing the percent bound values for the upper and lower limits of the range of concentrations examined (1).   

Only single activity values, indicating an average, were used in the generation of this model.

The protein samples used in binding studies are takes from healthy individuals because there are several disease states that can affect the protein binding of drugs.  Examples include  hepatic diseases that alter the concentration of albumin in the plasma and uremia that can cause changes in the binding affinity of some drugs (1).

(1) J.G. Hardman and L. E. Limbird (Eds.)  Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill Publications, New York (1996) appendix.

Interaction with Plasma Proteins

Depending upon whether the drug is a weak or strong acid or base, or is neutral, it can bind to a single blood protein, to multiple proteins (e.g. serum albumin, acid-glycoprotein (AGP) or lipoproteins).  The most significant protein involved in the binding of drugs is albumin, which comprises more than half of all blood proteins.  Albumin can interact with acidic or basic drugs in the plasma by van der Waals dispersion forces, hydrophobic bonding, hydrogen bonding, and ionic interactions (2).  AGP interacts with mainly with basic entities whereas lipoproteins bind both basic and neutral drugs.

The extent to which a drug is bound to plasma proteins can affect the distribution of the drug in several ways.  The drug/protein complex does not permeate phospholipid bilayers, including capillary membranes, glomerular membranes in the nephrons, and the blood brain barrier (2).  Bound drugs are also less available to the enzymes involved in first-pass metabolism.  After much of the free drug has been cleared by the metabolic and excretory processes, the reversible drug/protein complex serves as a depot to replenish the concentration in vivo.

For these reasons, drugs with high protein binding activity values tend to have a greater half-life compared to those with lower values.  The prolonged activity resulting from these factors may be desirable, or may promote the emergence of undesirable side effects

(2)  W. O. Foye, Principles of Medicinal Chemistry, 3rd Edition, Lea and Febiger, Philadelphia (1998) 33.

Data Sources used for CSPB

Sources for Experimental Protein Binding Values

The activity values used in the generation of this model were taken from the sources lister below. 

There was sufficient agreement of values reported for the same compound to justify combining the data from these sources.

    The Pharmacological Basis of Therapeutics, 9th Edition, appendix

    AHFS Drug Information

    Nurse's Drug Guide

    Allgemeine Pharmakologie und Toxikologie

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