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From the 13 January 1997 issue of Smart Drug News [v5n6]. Copyright (c) 1997, 2009. All rights reserved.

The Lock-and-Key Model

The interaction between a receptor (which is sometimes an enzyme) and a drug (a nutrient, plant compound or pharmaceutical substance that interacts with the receptor) depends on the complementary (matched) shape of the interacting surfaces. In this diagram, four different shapes are presented. Drug A has no fit at all and would have minimal interaction with the receptor. Drug B has some degree of fit, but it is not optimized. The triangle shape on the left and the block on the right are smaller than optimum. So drug B can have some affinity for the receptor. Drug C is optimized for the receptor. The surfaces are exact complements of each other. Drug C has the highest affinity for the receptor and causes a total biological effect. It is called a full agonist.

If the middle (round) shape is responsible for activating the receptor (i.e., producing the biological effect), then drug B’s near fit would cause some degree of biological response and would be considered a partial agonist. Since drug D is missing this feature entirely, it would be an example of an antagonist, a drug which 1) fits the receptor without causing a biological effect and also 2)prevents or inhibits the binding of drugs B and C which would otherwise cause biological effects).

The Importance of Electrical Charge

Shape is not the only factor influencing receptor-drug interaction. The surfaces of molecules can have different charges (positive or negative) and they can be hydrophillic (water attracting) or hydrophobic (water repelling). In the illustration detail, examples of different charge distributions are presented for drug C. Drug C1 fits the receptor exactly because the charges are opposite on adjacent surfaces. In other words, the presence of positive charges on one surface is complemented by negative charges on the opposite surface. This provides powerful attractive forces that make for strong receptor-drug binding.

Despite it’s identical shape, drug C2 does not fit the receptor. The triangular shape has positive charges repelling positive charges, and negative charges repelling negative charges. This seriously destabilizes the receptor-drug binding. Furthermore, the square shape (right) on drug C2 has a negatively charged surface (which is hydrophilic) up against a non-charged (hydrophobic) region of the receptor. This also destabilizes binding.

A good example of a hydrophobic surface is wax. If you put a drop of water on a waxed surface, it beads up. Even if you smear the water onto the surface, it still beads up. This is quite different from how a drop of water behaves when dropped onto the surface of a soapy (hydrophilic) dinner plate. The water drop quickly spreads out in a thin layer on the surface of the plate.

The combination of shape, charge and hydrophobicity provides a great deal of uniqueness to surfaces. This uniqueness allows for a great deal of specificity in receptor-drug interactions. ——SWF