Bohdan Waszkowycz | PubMed Health

PubMed2002

PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors.

In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.

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PubMed2002

Structure-based approaches to drug design and virtual screening.

Structure-based design has made an important contribution to drug discovery for many years. Recently, the increasing availability of structural data and the affordability of high-performance computing platforms have broadened the applicability of these methods. In particular, virtual screening has been adopted as an effective paradigm for lead discovery that fits in well alongside high-throughput screening programs. Structure-based virtual screening relies on fast and accurate computational methods for the prediction of receptor-ligand binding modes and binding affinities. In this paper, recent technical advances in the field of molecular docking and de novo design are reviewed, in particular, the development of flexible receptor models, docking of combinatorial libraries and novel scoring methods.

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