Chemical Library Design

Volume 685 of the series Methods in Molecular Biology pp 111-133


Application of QSAR and Shape Pharmacophore Modeling Approaches for Targeted Chemical Library Design

  • Jerry O. EbalunodeAffiliated withDepartment of Pharmaceutical Sciences, BRITE Institute, North Carolina Center University Email author 
  • , Weifan ZhengAffiliated withDepartment of Pharmaceutical Sciences, BRITE Institute, North Carolina Center University
  • , Alexander TropshaAffiliated withLaboratory for Molecular Modeling and Carolina Center for Exploratory Cheminformatics Research, School of Pharmacy, University of North Carolina at Chapel Hill

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Optimization of chemical library composition affords more efficient identification of hits from biological screening experiments. The optimization could be achieved through rational selection of reagents used in combinatorial library synthesis. However, with a rapid advent of parallel synthesis methods and availability of millions of compounds synthesized by many vendors, it may be more efficient to design targeted libraries by means of virtual screening of commercial compound collections. This chapter reviews the application of advanced cheminformatics approaches such as quantitative structure–activity relationships (QSAR) and pharmacophore modeling (both ligand and structure based) for virtual screening. Both approaches rely on empirical SAR data to build models; thus, the emphasis is placed on achieving models of the highest rigor and external predictive power. We present several examples of successful applications of both approaches for virtual screening to illustrate their utility. We suggest that the expert use of both QSAR and pharmacophore models, either independently or in combination, enables users to achieve targeted libraries enriched with experimentally confirmed hit compounds.

Key words

QSAR modeling pharmacophore modeling model validation virtual screening