Compound Ranking Based on Fuzzy Three-Dimensional Similarity Improves the Performance of Docking into Homology Models of G-Protein-Coupled Receptors

ACS Omega
Andrew Anighoro, Jürgen Bajorath

Abstract

Ligand docking into homology models of G-protein-coupled receptors (GPCRs) is a widely used approach in computational compound screening. The generation of "double-hypothetical" models of ligand-target complexes has intrinsic accuracy limitations that further complicate compound ranking and selection compared to those of X-ray structures. Given these uncertainties, we have explored "fuzzy 3D similarity" between hypothetical binding modes of known ligands in homology models and docking poses of database compounds as an alternative to conventional scoring schemes. Therefore, GPCR homology models at varying accuracy levels were generated and used for docking. Increases in recall performance were observed for fuzzy 3D similarity ranking using single or multiple ligand poses compared to that of conventional scoring functions and interaction fingerprints. Fuzzy similarity ranking was also successfully applied to docking into an external model of a GPCR for which no experimental structure is currently available. Taken together, our results indicate that the use of putative ligand poses, albeit approximate at best, increases the odds of identifying active compounds in docking screens of GPCR homology models.

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Nov 3, 2004·Nature Reviews. Drug Discovery·Douglas B KitchenJürgen Bajorath
Jan 24, 2006·Journal of Chemical Information and Modeling·Visvaldas KairysMichael K Gilson
Dec 26, 2006·Biochimica Et Biophysica Acta·Brian K Kobilka
Feb 10, 2007·Journal of Chemical Information and Modeling·Jean-François Truchon, Christopher I Bayly
May 10, 2007·Journal of Molecular Modeling·Philippe Ferrara, Edgar Jacoby
Nov 27, 2007·British Journal of Pharmacology·N MoitessierC R Corbeil
Jan 16, 2008·Trends in Pharmacological Sciences·Brian Kobilka, Gebhard F X Schertler
Apr 30, 2008·Journal of Chemical Information and Modeling·Sebastian RadestockSteffen Renner
May 22, 2009·Nature·Daniel M RosenbaumBrian K Kobilka
Oct 23, 2009·Journal of Chemical Information and Modeling·Hao FanAndrej Sali
Aug 24, 2010·Physical Chemistry Chemical Physics : PCCP·Sheng-You HuangXiaoqin Zou
Sep 20, 2011·Nature Chemical Biology·Jens CarlssonBrian K Shoichet
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins
Apr 17, 2012·Trends in Pharmacological Sciences·Brian K Shoichet, Brian K Kobilka
Jun 22, 2012·Journal of Medicinal Chemistry·Michael M MysingerBrian K Shoichet
Jul 17, 2012·Science·Wei LiuRaymond C Stevens
Sep 29, 2012·Current Pharmaceutical Design·Jui-Chih Wang, Jung-Hsin Lin
Mar 15, 2013·Journal of Chemical Information and Modeling·Andrew Anighoro, Giulio Rastelli
Apr 24, 2013·Alzheimer's Research & Therapy·María Javier Ramírez
May 9, 2013·Current Medicinal Chemistry·A Lavecchia, C Di Giovanni
May 28, 2013·Journal of Chemical Information and Modeling·Matthias R BauerFrank M Boeckler
Jun 21, 2013·Journal of Chemical Information and Modeling·G Madhavi SastryWoody Sherman
Sep 21, 2013·Drug Discovery Today. Technologies·Malgorzata N Drwal, Renate Griffith
Oct 25, 2013·Journal of Medicinal Chemistry·Gerald MaggioraJürgen Bajorath
Dec 21, 2013·Science·Wei LiuVadim Cherezov
Jun 1, 2014·Journal of Chemical Information and Modeling·Fabio Broccatelli, Nathan Brown
Aug 5, 2014·Bioorganic & Medicinal Chemistry Letters·Christofer S Tautermann
May 6, 2015·Journal of Computer-aided Molecular Design·Ann E Cleves, Ajay N Jain
Jun 23, 2015·Journal of Medicinal Chemistry·Delphine KarilaChristophe Rochais
Nov 20, 2015·Nucleic Acids Research·Vignir IsbergDavid E Gloriam
Feb 26, 2016·Journal of Medicinal Chemistry·John J Irwin, Brian K Shoichet
Feb 27, 2016·Journal of Chemical Information and Modeling·Andrew Anighoro, Jürgen Bajorath
Jun 24, 2016·Journal of Computer-aided Molecular Design·Andrew Anighoro, Jürgen Bajorath
Jun 25, 2016·Scientific Reports·Albert J KooistraChris de Graaf
Sep 9, 2016·Journal of Cheminformatics·Sakari LättiOlli T Pentikäinen

❮ Previous
Next ❯

Citations

Jul 4, 2018·Journal of Computer-aided Molecular Design·Tomoyuki Miyao, Jürgen Bajorath
Oct 21, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Javier VázquezF Javier Luque
May 5, 2020·Journal of Chemical Information and Modeling·Javier VazquezF Javier Luque

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray

Software Mentioned

MOE
Clustal Omega
DUD
MODELLER
DEKOIS
Molecular Operating Environment ( MOE )

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.