Modulation of biomolecular interactions with complex-binding small molecules.

Although numerous biomolecular interactions have been identified as potential targets for the development of therapeutic agents, modulation of these interactions with small molecules has historically been considered an extremely difficult task. This difficulty is largely due to the low effectiveness of the traditionally used competitive approaches in which inhibitors are designed and screened for their ability to block biomolecules from establishing contacts with their targets. We propose a novel approach to modulate biomolecular interactions by de novo structure-based design of noncompetitive small molecules that bind to the intermolecular complexes and make molecular contacts with both interacting partners. Similar complex-binding mechanism has been observed and well documented for many natural compounds that bind to protein-protein, protein-DNA or protein-small molecule complexes. To implement the paradigm for structure-based drug design, we have developed a complex-binding modulation (CBM) algorithm for the rational design of compounds (CBM compounds) that can affect biomolecular interactions by binding to the intermolecular pockets or cavities of biomolecular complexes. In this paper, we describe our methodology used to design the CBM compounds and to study their effects on biomolecular interactions including protein-protein and protein-small molecule interactions.