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

TY - JOUR

T1 - Missing Fragments: Detecting Cooperative Binding in Fragment-Based Drug Design

AU - Nair, Pramod C.

AU - Malde, Alpeshkumar K.

AU - Drinkwater, Nyssa

AU - Mark, Alan E.

PY - 2012/4/12

Y1 - 2012/4/12

N2 - 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.

AB - 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.

U2 - 10.1021/ml300015u

DO - 10.1021/ml300015u

M3 - Article

VL - 3

SP - 322

EP - 326

JO - Acs Medicinal Chemistry Letters

JF - Acs Medicinal Chemistry Letters

IS - 4

ER -