De novo inhibitor design is being pursued with the molecule-growing program BOMB. Molecules are constructed by adding layers of substituents to a core that has been placed in a binding site. The substituents can be linked together in alternative �topologies�. BOMB includes a library of ca. 700 possible substituents including most common heterocycles. The substituents are organized in groupings Gi such as 5Het for 5-membered ring heterocycles. For a typical BOMB run, the user specifies the core, the topology, and the Gi. These define a �template�, which is equivalent to a combinatorial library, and all molecules corresponding to the template are grown. For each grown molecule, a thorough conformational search is performed. The dihedral angles for the conformer are optimized along with its position and orientation using OPLS-AA force fields. The resultant lowest-energy conformer is evaluated with a scoring function to predict activity. Applications are illustrated and areas for improvement are considered. Related issues that affect accuracy are also noted including the placement of water moelcules in protein binding sites.

De novo molecular design: Successes and challenges

243rd National Meeting (2012)

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