Enabling drug discovery project decisions with integrated computational chemistry and informatics.

Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training.

Coupling structure-based design with combinatorial chemistry: application of active site derived pharmacophores with informative library design.

Protein structural information is combined with combinatorial library design in the following protocol. Active site maps are generated from protein structures. All possible 2-, 3- and 4-point pharmacophores are enumerated from the active site map and encoded as bit strings. The pharmacophores define a design space that can be used to select compounds using an informative library design tool. The method was evaluated against a collection of compounds assayed previously against a cyclin-dependent kinase target, CDK-2, starting with 23 X-ray co-crystal structures. Performance was assessed based on the number of active scaffolds selected after four rounds of iterative informative library design. The method selects compounds from 12 out of the 15 active scaffolds from the CDK-2 library and outperforms a two-dimensional similarity search and docking calculations.