With the premise that radical new departures in bioorganic chemistry are unlikely to result from further elaboration of macrocyclic model systems, we have embarked on a program to devise catalysts from new molecular shapes. Accordingly, we have developed structural motifs from which a variety of cleft-like molecules can be prepared in modular fashion. These feature catalytically useful functional groups which converge to provide complements to transition states of high-energy intermediates. They resemble a number of enzyme active sites in their acid-base character and presentation of functional groups. These are poised for concerted catalysis, but kept from direct interaction through the use of rigid spacer elements. Realistic arrays are developed for synthetic nucleases, proteases, dismutases and oxobridged diiron centers. It is expected that these studies will continue to contribute to the mechanistic and structural foundations of rational drug design.
