Journal of Computer-Aided Molecular Design

, Volume 21, Issue 1, pp 113–119

Lead-like, drug-like or “Pub-like”: how different are they?

  • Tudor I. Oprea
  • Tharun Kumar Allu
  • Dan C. Fara
  • Ramona F. Rad
  • Lili Ostopovici
  • Cristian G. Bologa
Original Paper

DOI: 10.1007/s10822-007-9105-3

Cite this article as:
Oprea, T.I., Allu, T.K., Fara, D.C. et al. J Comput Aided Mol Des (2007) 21: 113. doi:10.1007/s10822-007-9105-3


Academic and industrial research continues to be focused on discovering new classes of compounds based on HTS. Post-HTS analyses need to prioritize compounds that are progressed to chemical probe or lead status. We report trends in probe, lead and drug discovery by examining the following categories of compounds: 385 leads and the 541 drugs that emerged from them; “active” (152) and “inactive” (1488) compounds from the Molecular Libraries Initiative Small Molecule Repository (MLSMR) tested by HTS; “active” (46) and “inactive” (72) compounds from Nature Chemical Biology (NCB) tested by HTS; compounds in the drug development phase (I, II, III and launched), as indexed in MDDR; and medicinal chemistry compounds from WOMBAT, separated into high-activity (5,784 compounds with nanomolar activity or better) and low-activity (30,690 with micromolar activity or less). We examined Molecular weight (MW), molecular complexity, flexibility, the number of hydrogen bond donors and acceptors, LogP—the octanol/water partition coefficient estimated by ClogP and ALOGPS), LogSw (intrinsic water solubility, estimated by ALOGPS) and the number of Rule of five (Ro5) criteria violations. Based on the 50% and 90% distribution moments of the above properties, there were no significant difference between leads of known drugs and “actives” from MLSMR or NCB (chemical probes). “Inactives” from NCB and MLSMR were also found to exhibit similar properties. From these combined sets, we conclude that “Actives” (569 compounds) are less complex, less flexible, and more soluble than drugs (1,651 drugs), and significantly smaller, less complex, less hydrophobic and more soluble than the 5,784 high-activity WOMBAT compounds. These trends indicate that chemical probes are similar to leads with respect to some properties, e.g., complexity, solubility, and hydrophobicity.


Chemical probes Combinatorial chemistry Computer chemistry Database filtering Druglike Drug research Hydrogen bonds Lead discovery Leadlike MLSCN MLSMR Molecular complexity Property distribution Pub-like PubChem “Rule of 5” test WOMBAT 



Program available from, Germany


LogP calculated with the Biobyte program


Number of H-bond acceptors


Number of H-bond donors


The logarithm of the octanol-water partition coefficient


MDL Drug Data Report


Molecular Libraries and Imaging initiative


The MLI Screening Centers Network


The MLI Small Molecule Repository


Molecular weight


Nature Chemical Biology


National Institutes of Health


Number of rings


Lipinski’s Rule of Five


Number of non-terminal flexible bonds


Simple Molecular Complexity Metric


Simplified Molecular Input Line Entry Specification


Sum of nitrogen and oxygen atoms


Tetko’s LogP, calculated with ALOGPS


Tetko’s logarithm of the (molar) aqueous solubility, calculated with ALOGPS


WOrld of Molecular BioAcTivity database

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Tudor I. Oprea
    • 1
    • 2
  • Tharun Kumar Allu
    • 1
  • Dan C. Fara
    • 1
  • Ramona F. Rad
    • 3
  • Lili Ostopovici
    • 3
  • Cristian G. Bologa
    • 1
  1. 1.Division of Biocomputing, Department of Biochemistry and Molecular BiologyUniversity of New Mexico School of MedicineAlbuquerqueUSA
  2. 2.Sunset Molecular Discovery LLCSanta FeUSA
  3. 3.Romanian Academy Institute of ChemistryTimisoaraRomania

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