Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2

Autor: Teresa, Kaserer, Veronika, Temml, Zsofia, Kutil, Tomas, Vanek, Premysl, Landa, Daniela, Schuster
Rok vydání: 2014
Předmět:
Models
Molecular
Drug Evaluation
Preclinical
AA
arachidonic acid
PGE2
Prostaglandin E2
ECFP4
Extended-connectivity fingerprints 4
Docking
Method comparison
SEA
Similarity Ensemble Approach
MNA
multilevel neighborhoods of atoms
FCFP6
Functional-class fingerprints 6
HBD
hydrogen bond donor
Acc
accuracy
Tc
Tanimoto coefficient
Molecular Structure
R
ring feature
NI
negative ionizable feature
XVOL
exclusion volume
GFA
genetic function approximation
Cyclooxygenase
EE
early enrichment
HIV-1
human immunodeficiency virus 1
OEST
ROCS OpenEye shape Tanimoto
Original Article
DES
diethylstilbestrol
TP
true positive hits
WOMBAT
World of Molecular Bioactivity
ACE
angiotensin-converting enzyme
FN
false negative hits
FP
false positive hits
KEGG
Kyoto Encyclopedia of Genes and Genomes
Structure-Activity Relationship
Shape-based modeling
C
cation
TN
true negative hits
Humans
Cyclooxygenase Inhibitors
ROCS
Rapid Overlay of Chemical Structures
SERMs
selective estrogen receptor modulators
Pharmacophore modeling
Ar
aromatic feature
OE
overall enrichment
Dose-Response Relationship
Drug
MB
metal binding feature
OECS
ROCS OpenEye ComboScore
DUD
Directory of Useful Decoys
m. p.
melting point
COX
cyclooxygenase
H
hydrophobic feature
Cyclooxygenase 2
HBA
hydrogen bond acceptor
Cyclooxygenase 1
PASS
Prediction of Activity Spectra for Substances
A
anion
PDB
Protein Databank
2D similarity-based search
Zdroj: European Journal of Medicinal Chemistry
ISSN: 1768-3254
Popis: Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.
Graphical abstract
Highlights • Selected common virtual screening tools were applied in parallel. • Top-ranked hits were investigated with bioactivity profiling tools. • Compounds were tested in vitro for COX activity. • The prospective performance of all applied programs was evaluated and compared.
Databáze: OpenAIRE
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