Interacting with GPCRs: Using Interaction Fingerprints
for Virtual Screening
Eelke
B. Lenselink
Willem Jespers
Herman W. T. van Vlijmen
Adriaan P. IJzerman
Gerard J. P. van Westen
10.1021/acs.jcim.6b00314.s001
https://acs.figshare.com/articles/journal_contribution/Interacting_with_GPCRs_Using_Interaction_Fingerprints_for_Virtual_Screening/3863058
The expanding number
of crystal structures of G protein-coupled
receptors (GPCRs) has increased the knowledge on receptor function
and their ability to recognize ligands. Although structure-based virtual
screening has been quite successful on GPCRs, scores obtained by docking
are typically not indicative for ligand affinity. Methods capturing
interactions between protein and ligand in a more explicit manner,
such as interaction fingerprints (IFPs), have been applied as an addition
or alternative to docking. Originally IFPs captured the interactions
of amino acid residues with ligands with specific definitions for
the various interaction types. More complex IFPs now capture atom–atom
interactions, such as in SYBYL, or fragment–fragment co-occurrences
such as in SPLIF. Overall, most of the IFPs have been studied in comparison
with docking in retrospective studies. For GPCRs it remains unclear
which IFP should be used, if at all, and in what manner. Thus, the
performance between five different IFPs was compared on five different
representative GPCRs, including several extensions of the original
implementations,. Results show that the more detailed IFPs, SYBYL
and SPLIF, perform better than the other IFPs (Deng, Credo, and Elements).
SPLIF was further tuned based on the number of poses, fingerprint
similarity coefficient, and using an ensemble of structures. Enrichments
were obtained that were significantly higher than initial enrichments
and those obtained by 2D-similarity. With the increase in available
crystal structures for GPCRs, and given that IFPs such as SPLIF enhance
enrichment in virtual screens, it is anticipated that IFPs will be
used in conjunction with docking, especially for GPCRs with a large
binding pocket.
2016-09-14 00:00:00
IFP
crystal structures
docking
ligand
GPCR
G protein-coupled receptors
SPLIF
fingerprint similarity coefficient
interaction
SYBYL