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

Abstract

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.

Keywords

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 

Abbreviations

ALOGPS

Program available from vcclab.org, Germany

ClogP

LogP calculated with the Biobyte program

HAC

Number of H-bond acceptors

HDO

Number of H-bond donors

LogP

The logarithm of the octanol-water partition coefficient

MDDR

MDL Drug Data Report

MLI

Molecular Libraries and Imaging initiative

MLSCN

The MLI Screening Centers Network

MLSMR

The MLI Small Molecule Repository

MW

Molecular weight

NCB

Nature Chemical Biology

NIH

National Institutes of Health

RNG

Number of rings

Ro5

Lipinski’s Rule of Five

RTB

Number of non-terminal flexible bonds

SMCM

Simple Molecular Complexity Metric

SMILES

Simplified Molecular Input Line Entry Specification

SumNO

Sum of nitrogen and oxygen atoms

TlogP

Tetko’s LogP, calculated with ALOGPS

TlogSw

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

WOMBAT/WB

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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