title: Missing fragments: detecting cooperative binding in fragment-based drug design.
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.
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB) and Institute for Molecular Bioscience (IMB), The University of Queensland (UQ) , St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Pramod C
authors.initials: PC
authors.lastname: Nair
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB) and Institute for Molecular Bioscience (IMB), The University of Queensland (UQ) , St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Alpeshkumar K
authors.initials: AK
authors.lastname: Malde
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB) and Institute for Molecular Bioscience (IMB), The University of Queensland (UQ) , St Lucia Campus, Brisbane, QLD 4072, Australia ; Randall Division of Cell and Molecular Biophysics, King's College London , London, SE1 1UL, United Kingdom.
authors.forename: Nyssa
authors.initials: N
authors.lastname: Drinkwater
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB) and Institute for Molecular Bioscience (IMB), The University of Queensland (UQ) , St Lucia Campus, Brisbane, QLD 4072, Australia ; School of Chemistry and Molecular Biosciences (SCMB) and Institute for Molecular Bioscience (IMB), The University of Queensland (UQ) , St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Mark
keywords: drug binding; free energy calculations; molecular dynamics; molecular fragments; phenylethanolamine N-methyltransferase (PNMT)