Collaborations
 

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Bob led two major collaborative projects while at Simulations Plus: The successful design, preparation and testing of a set of novel antimalarial aminoquinolone derivatives that involving synthesis by Kalexsyn, Inc., and testing against live parasites at the University of California, Riverside and by the Tres Cantos labs at GlaxoSmithKline under the aegis of the Medicines for Malaria Venture (MMV). Design, synthesis and testing activities with a team of medicinal chemists from a leading pharmaceutical company that provided proof-of-concept support for SLP's AI-driven drug design (AIDD) module in ADMET Predictor (manuscript in preparation). You can get a sense of what he learned about collaborations over his years at Tripos by looking through a talk he gave at the ACS National Meeting early in 2008. He participated in many different Tripos collaborations over the years, including with: Biovitrum AB (2003-2004): Set out to develop a successor to the GASP program for pharmacophore elucidation. This led to the development of GALAHAD, which splits the alignment problem into two separate parts – alignment in the internal coordinate space using a novel genetic algorithm (GA) and subsequent by alignment in Cartesian space.  Doing so makes it possible to recognize fuzzy pharmacophores (where partial match constraints apply to some features but not all) and avoids the need for template ligands.  University of Sheffield (2002-2004): Provided direction to Dr. Nicola Richmond for her Tripos-funded post-doctoral work in Peter Willett’s laboratory. This led to the development of the LAMDA alignment program, which combines linear assignment methodology with incremental build-up of hypermolecular templates to align rigid molecular structures. Novo Nordisk A/S (2001-2003):  Developed fast pharmacophore multiplet (TUPLET) technology, which allows ligands to be analyzed in terms of relationships between their constituent pharmacophoric substructures.  A novel approach to encoding makes it possible to very efficiently generate and manipulate fingerprints in a compressed form (bitmaps) rather than as cumbersome bitsets. A new similarity measure – the stochastic cosine – was developed that allows meaningful comparisons to be made between truly independent ensembles of conformations. This alleviated the need to restrict the torsional space explored to large, fixed increments that had limited earlier approaches. Parke-Davis (2000-2003): Developed selection, clustering and visualization tools for use by the biologists and chemists involved in lead triage for drug discovery and development, ultimately leading to the HTS DataMiner program. A separate collaboration with Parke-Davis in 2002 produced the OptiDock combinatorial docking program, which combines OptiSim selection with FlexX. Other programs position the scaffold and work outwards from there; OptiDock optimizes scaffold placements by docking a sample of individual products, thereby giving more accurate results. Pfizer, Inc. (1998-2001): Tripos was commissioned to develop a genetic algorithm wherein each chromosome represents a UNITY flexible 3D search query, with each gene encoding a separate feature from the query. The program successfully generated ensembles of complementary partial-match queries from high-throughput screening (HTS) data.  In collaboration with a major European agrochemicals company, we recently incorporated a multi-objective scoring function into the GA to resolve the underlying conflict between query coverage and discrimination. The consensus scoring program CSCORE also grew out of this collaboration. Worked with Tripos Discovery Research clients to develop protein kinase inhibitors and DNA minor groove binders. In many ways, Bob's years at Monsanto were one long collaboration, in part because the synthesis chemists, screeners, biologists and field scientists in an agrochemicals company have always had to work very closely together to get a candidate through the commercialization process. The situation was very similar to the cross-disciplinary development teams now common in biotechs and pharmaceutical companies, but contrasted sharply with the minimal interaction between people in different "silos" that used to prevail at most large pharmaceutical companies at the time. As he moved from physiology to herbicide synthesis to screening to fungicide synthesis, the hat Bob wore changed but the cooperative environment he worked in did not.