Missing Fragments: Detecting Cooperative Binding in Fragment-Based Drug Design

Pramod Nair, Alpeshkumar Malde, Nyssa Drinkwater, Alan Mark

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    19 Citations (Scopus)

    Abstract

    The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind to alternate subsites within a given binding pocket leading to cooperative binding when linked. In this study, the binding of fragments to human phenylethanolamine N-methyltransferase is used to illustrate how (a) current protocols may fail to detect fragments that bind cooperatively, (b) theoretical approaches can be used to validate potential hits, and (c) apparent false positives obtained when screening against cocktails of fragments may in fact indicate promising leads.

    Original languageEnglish
    Pages (from-to)322-326
    Number of pages5
    JournalACS Medicinal Chemistry Letters
    Volume3
    Issue number4
    DOIs
    Publication statusPublished - 12 Apr 2012

    Keywords

    • drug binding
    • free energy calculations
    • molecular dynamics
    • molecular fragments
    • phenylethanolamine N-methyltransferase (PNMT)

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