STRUCTURAL-ANALYSIS OF RICIN AND IMPLICATIONS FOR INHIBITOR DESIGN

Ricin is a potent cytotoxin with experimental and clinical uses; it ha s also been used as a poison. There is considerable interest in identi fying or designing inhibitors of the toxin that could be administered as antidotes. The X-ray structure of ricin A-chain is known and a plau sible mechanism of action has been proposed. This provides a structura l and chemical framework around which inhibitors could be designed; su ch a structure-based project is underway. Computer programs such as DO CK, GRID, SYBYL, and CHEMX have been used to map the ricin A-chain bin ding site and to search for potential inhibitors. Inhibitor candidates can be assayed kinetically in a protein synthesis assay and binding c an be observed crystallographically. Taken together, a workable search algorithm has been developed and initial tests indicate that at least one ricin A-chain inhibitor, pteroic acid, has been identified. Copyr ight (C) 1996 Elsevier Science Ltd