HEMOGLOBIN AS A RECEPTOR OF DRUGS AND PEPTIDES - X-RAY STUDIES OF THE STEREOCHEMISTRY OF BINDING

In an attempt to establish a stereochemical rationale for the development of drugs against sickle cell anemia, we have crystallized human deoxyhemoglobin with the antihyperlipoproteinemia drug bezafibrate (I), with the diuretic drug ethacrynic acid (III), with succinyl-L-tryptophan-L-tryptophan (IV), and with p-bromobenzyloxyacetic acid (V) and have determined the structures of the complexes by X-ray analysis. Our results show that these compounds seek out niches in the protein where their stereochemistry of binding is determined by the available van der Waals space and, within that space, by a tendency to maximize electrostatic interactions. These range from strong hydrogen bonds to weakly polar interactions between halogens and aromatic quadrupoles. Another large part of the binding energy is due to hydrophobic effects. The binding site of p-bromobenzyloxyacetic acid lies in the interior of the .alpha.-chain, in a position hitherto believed to be filled by close-packed side chains of the globin. The binding of these varied compounds induces small distortions in the hemoglobin molecule which affect the solubility of deoxyhemoglobin S. Ethacrynic acid, p-bromobenzylacetic acid, and succinyl-L-tryptophan-L-tryptophan increase and bezafibrate reduces the solubility of deoxyhemoglobin S. Ethacrynic acid increases while bezafibrate and succinyl-L-tryptophan-L-tryptophan lower the oxygen affinity of hemoglobin A. .pi.-Bromobenzyloxyacetic acid does not affect it.