Format

Send to

Choose Destination
J Chem Inf Model. 2017 Feb 27;57(2):311-321. doi: 10.1021/acs.jcim.6b00263. Epub 2017 Jan 18.

From Homology Models to a Set of Predictive Binding Pockets-a 5-HT1A Receptor Case Study.

Author information

1
Institute of Pharmacology, Polish Academy of Sciences , 12 Smetna Street, 31-343 Kraków, Poland.
2
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego , 9500 Gilman Drive, MC 0747 La Jolla, California 92093-0747, United States.
3
Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
4
Department of Cell Biology, National Medicines Institute , 30/34 Chełmska Street, 00-725 Warszawa, Poland.

Abstract

Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the X-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including the endogenous neurotransmitter-serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1A receptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform. Starting from a homology template and set of known actives, the method introduces receptor flexibility via Normal Mode Analysis and Monte Carlo sampling, to generate a subset of pockets that display enriched discrimination of actives from inactives in retrospective docking. Here, we thoroughly investigated the repercussions of using different protein templates and the effect of compound selection on screening performance. Finally, the best resulting protein models were applied prospectively in a large virtual screening campaign, in which two new active compounds were identified that were chemically distinct from those described in the literature.

PMID:
28055203
PMCID:
PMC5361891
DOI:
10.1021/acs.jcim.6b00263
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center