Journal of Computer-Aided Molecular Design

, Volume 27, Issue 9, pp 783–792 | Cite as

The importance of molecular complexity in the design of screening libraries

  • Shahul H. Nilar
  • Ngai Ling Ma
  • Thomas H. Keller


The one-dimensional model of Hann et al. (J Chem Inf Comput Sci 41(3):856–864) has been extended to include reverse binding and wrap-around interaction modes between the protein and ligand to explore the complete combinatorial matrix of molecular recognition. The cumulative distribution function of the Maxwell–Boltzmann distribution has been used to calculate the probability of measuring the sensitivity of the interactions as the asymptotic limits of the distribution better describe the behavior of the interactions under experimental conditions. Based on our model, we hypothesized that molecules of lower complexity are preferred for target based screening campaigns, while augmenting such a library with moieties of moderate complexities maybe better suited for phenotypic screens. The validity of the hypothesis has been assessed via the analysis of the hit rate profiles for four ChemBL datasets for enzymatic and phenotypic screens.


Molecular complexity Selectivity Sensitivity Intermolecular interaction 



Shahul Nilar thanks Dr. Richard Lewis of the Novartis Institute for Biomedical Research, Basel, Switzerland and Dr. Peter Gedeck of the Novartis Institute for Tropical Diseases, Singapore for critically reading the manuscript and providing helpful suggestions. Dr. Ivica Res’s help with some of the programming aspects of this work is gratefully acknowledged.


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Shahul H. Nilar
    • 1
  • Ngai Ling Ma
    • 1
  • Thomas H. Keller
    • 1
    • 2
  1. 1.Novartis Institute for Tropical DiseasesSingaporeSingapore
  2. 2.Experimental Therapeutic Center, Agency for Science, Technology and ResearchSingaporeSingapore

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