MODELING DRUG-MELANIN INTERACTION WITH THEORETICAL LINEAR SOLVATION ENERGY RELATIONSHIPS

The affinity of drugs and other xenobiotic agents for melanin is a wel l-known phenomenon, often occurring with serious physiological consequ ences. For example, the interaction of anti-psychotic drugs with neuro melanin may play a pivotal role in the induction of extrapyramidal mov ement disorders associated with the chronic administration of phenothi azine and other neuroleptic agents. Little, however, is known about th e complete nature of melanin-drug binding and the impact of these inte ractions on the physico-chemical properties of melanin. Data, such as binding affinities, can be analyzed using recently developed computati onal methods that combine mathematical models of chemical structure wi th statistical analysis. In particular, theoretical linear solvation e nergy relationships provide a convenient model for understanding and p redicting biological, chemical, and physical properties. By using this modeling technique, drug-melanin binding of a set of 16 compounds has been analyzed with correlation analysis and a set of theoretical mole cular parameters in order to better understand and characterize drug-m elanin interactions. The resulting correlation equation supports a cha rge transfer model for drug-melanin complex formation and can also be used to estimate binding constants for related compounds.