Skip to main content

Advertisement

Structure-activity relationship analysis on the basis of matched molecular pairs

Matched molecular pairs (MMPs), i.e., pairs of compounds that are related to each other by a specific molecular transformation, have become an integral tool of drug discovery [1, 2]. Generally spoken, matched molecular pair analysis (MMPA) aims at the extraction of all MMPs from a set of compounds and their association with calculated or measured property changes. Using public bioactivity data, we have used MMPs as a consistent reference framework to identify sets of chemical replacements that either have the propensity to induce large-magnitude potency changes or tend to retain compound potency across diverse targets [3, 4]. Furthermore, we have extended the concept of MMPs to matched molecular series, i.e., analog series with different molecular core structures but corresponding substitution patterns [5, 6]. The identification of series with alternative core structures but similar SAR trends is highly relevant for lead optimization where SAR information from one series that has been explored historically is ideally used to guide compound design efforts for a new chemotype [6].

References

  1. 1.

    Griffen E, Leach AG, Robb GR, Warner DJ: Matched molecular pairs as a medicinal chemistry tool. J Med Chem. 2011, 54: 7739-7750. 10.1021/jm200452d.

  2. 2.

    Dossetter AG, Griffen EJ, Leach AG: Matched molecular pair analysis in drug discovery. Drug Discov Today. 2013, 18: 724-731. 10.1016/j.drudis.2013.03.003.

  3. 3.

    Wassermann AM, Bajorath J: Chemical substitutions that introduce activity cliffs across different compound classes and biological targets. J Chem Inf Model. 2010, 50: 1248-1256. 10.1021/ci1001845.

  4. 4.

    Wassermann AM, Bajorath J: Large-scale exploration of bioisosteric replacements on the basis of matched molecular pairs. Future Med Chem. 2011, 3: 425-436. 10.4155/fmc.10.293.

  5. 5.

    Wawer M, Bajorath J: Local structural changes, global data views: graphical substructure-activity relationship trailing. J Med Chem. 2011, 54: 2944-2951. 10.1021/jm200026b.

  6. 6.

    Wassermann AM, Bajorath J: A data mining method to facilitate SAR transfer. J Chem Inf Model. 2011, 51: 1857-1866. 10.1021/ci200254k.

Download references

Author information

Correspondence to Anne Mai Wassermann.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Keywords

  • Core Structure
  • Lead Optimization
  • Reference Framework
  • Molecular Pair
  • Molecular Core