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Using Cheminformatics in Drug Discovery

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Part of the Handbook of Experimental Pharmacology book series (HEP,volume 232)


This chapter illustrates how cheminformatics can be applied to designing novel compounds that are active at the primary target and have good predicted ADMET properties. Examples of various cheminformatics techniques are illustrated in the process of designing inhibitors that inhibit both cyclooxygenase isoforms but are more potent toward COX-2. The first step in the process is to create a knowledge database of cyclooxygenase inhibitors in the public domain. This data was analyzed to find activity cliffs – small structural changes that result in drastic changes in potency. Additional cyclooxygenase potency and selectivity trends were obtained using matched molecular pair analysis. QSAR models were then developed to predict cyclooxygenase potency and selectivity. Next, computational algorithms were used to generate novel scaffolds starting from known cyclooxygenase inhibitors. Nine virtual libraries containing 240 compounds each were constructed. Predictions from the cyclooxygenase QSAR models were used to eliminate molecules with undesirable potency or selectivity. Additionally, the compounds were screened in silico for undesirable ADMET properties, e.g., low solubility, permeability, metabolic stability, or high toxicity, using a liability scoring system known as ADMET Risk™. Eight synthetic candidates were identified from this process after incorporating knowledge gained from activity cliff analysis. Four of the compounds were synthesized and tested to measure their COX-1 and COX-2 IC50 values as well as several ADME properties. The best compound, SLP0020, had a COX-1 IC50 of 770 nM and COX-2 IC50 of 130 nM.


  • Activity cliffs
  • Combinatorial design
  • COX-1
  • COX-2
  • Cyclooxygenase
  • Drug design
  • Matched molecular pairs
  • QSAR
  • QSPR
  • Scaffold hopping

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  • DOI: 10.1007/164_2015_23
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  1. 1.

    ADMET Predictor™ is distributed by Simulations Plus, Inc., Lancaster CA,

  2. 2.

    This section refers to the site as it existed in December of 2014.

  3. 3.

    MedChem Studio™ is distributed by Simulations Plus, Inc., Lancaster CA,

  4. 4.

    Eurofins Panlabs Inc. 15318 NE 95th Street, Redmond, WA 98052 USA, Tel (425) 895-8666

  5. 5.

    Absorption Systems, Exton PA 19341, Tel (610) 280-7300


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Correspondence to Michael S. Lawless .

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Lawless, M.S., Waldman, M., Fraczkiewicz, R., Clark, R.D. (2015). Using Cheminformatics in Drug Discovery. In: Nielsch, U., Fuhrmann, U., Jaroch, S. (eds) New Approaches to Drug Discovery. Handbook of Experimental Pharmacology, vol 232. Springer, Cham.

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