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.
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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
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Acknowledgement
This work was supported by National Institutes of Health grant U54 MH074425-01 (National Institutes of Health Molecular Libraries Initiative); and by the New Mexico Tobacco Settlement Fund (D.F. and T.I.O.). The calculated properties and SMILES for these 42,394 molecules will be available at the UNM Screening Center website (http://screening.health.unm.edu/). This paper is dedicated to Dr. Yvonne C. Martin, whose four decades of excellence in the areas of QSAR and computer-aided drug design has helped define the field of cheminformatics.
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Dedicated to Yvonne C. Martin on her 70th birthday.
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Oprea, T.I., Allu, T.K., Fara, D.C. et al. Lead-like, drug-like or “Pub-like”: how different are they?. J Comput Aided Mol Des 21, 113–119 (2007). https://doi.org/10.1007/s10822-007-9105-3
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DOI: https://doi.org/10.1007/s10822-007-9105-3