PMID- 24293134
OWN - NLM
STAT- MEDLINE
DCOM- 20140819
LR  - 20240330
IS  - 1573-4951 (Electronic)
IS  - 0920-654X (Print)
IS  - 0920-654X (Linking)
VI  - 27
IP  - 12
DP  - 2013 Dec
TI  - Development of purely structure-based pharmacophores for the topoisomerase 
      I-DNA-ligand binding pocket.
PG  - 1037-49
LID - 10.1007/s10822-013-9695-x [doi]
AB  - Purely structure-based pharmacophores (SBPs) are an alternative method to 
      ligand-based approaches and have the advantage of describing the entire 
      interaction capability of a binding pocket. Here, we present the development of 
      SBPs for topoisomerase I, an anticancer target with an unusual ligand binding 
      pocket consisting of protein and DNA atoms. Different approaches to cluster and 
      select pharmacophore features are investigated, including hierarchical clustering 
      and energy calculations. In addition, the performance of SBPs is evaluated 
      retrospectively and compared to the performance of ligand- and complex-based 
      pharmacophores. SBPs emerge as a valid method in virtual screening and a 
      complementary approach to ligand-focussed methods. The study further reveals that 
      the choice of pharmacophore feature clustering and selection methods has a large 
      impact on the virtual screening hit lists. A prospective application of the SBPs 
      in virtual screening reveals that they can be used successfully to identify novel 
      topoisomerase inhibitors.
FAU - Drwal, Malgorzata N
AU  - Drwal MN
AD  - Department of Pharmacology, School of Medical Sciences, University of New South 
      Wales, Sydney, NSW, 2052, Australia.
FAU - Agama, Keli
AU  - Agama K
FAU - Pommier, Yves
AU  - Pommier Y
FAU - Griffith, Renate
AU  - Griffith R
LA  - eng
GR  - Z01 BC007333/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131201
PL  - Netherlands
TA  - J Comput Aided Mol Des
JT  - Journal of computer-aided molecular design
JID - 8710425
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - 9007-49-2 (DNA)
RN  - EC 5.99.1.2 (DNA Topoisomerases, Type I)
RN  - EC 5.99.1.2 (TOP1 protein, human)
SB  - IM
MH  - DNA/chemistry/*metabolism
MH  - DNA Topoisomerases, Type I/*chemistry/*metabolism
MH  - *Drug Design
MH  - *Drug Discovery
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Inhibitors/*chemistry/pharmacology
MH  - *High-Throughput Screening Assays
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - Protein Binding
MH  - Protein Conformation
PMC - PMC7578780
MID - NIHMS1633089
EDAT- 2013/12/03 06:00
MHDA- 2014/08/20 06:00
PMCR- 2020/10/22
CRDT- 2013/12/03 06:00
PHST- 2013/09/11 00:00 [received]
PHST- 2013/11/26 00:00 [accepted]
PHST- 2013/12/03 06:00 [entrez]
PHST- 2013/12/03 06:00 [pubmed]
PHST- 2014/08/20 06:00 [medline]
PHST- 2020/10/22 00:00 [pmc-release]
AID - 10.1007/s10822-013-9695-x [doi]
PST - ppublish
SO  - J Comput Aided Mol Des. 2013 Dec;27(12):1037-49. doi: 10.1007/s10822-013-9695-x. 
      Epub 2013 Dec 1.