2021
Ballante, Flavio; Kooistra, Albert J; Kampen, Stefanie; de Graaf, Chris; Carlsson, Jens
Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You? Journal Article
In: Pharmacological Reviews, 73 , pp. 527-565, 2021, ISSN: 1521-0081.
Abstract | Links | BibTeX | Tags: GPCR, Molecular Docking, Review, Structure-Based Drug Design, Virtual Screening
@article{nokey,
title = {Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You?},
author = {Flavio Ballante and Albert J Kooistra and Stefanie Kampen and Chris de Graaf and Jens Carlsson},
url = {https://pharmrev.aspetjournals.org/content/73/4/527},
doi = {10.1124/pharmrev.120.000246},
issn = {1521-0081},
year = {2021},
date = {2021-12-14},
urldate = {2021-12-14},
journal = {Pharmacological Reviews},
volume = {73},
pages = {527-565},
abstract = {G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and are important therapeutic targets. During the last decade, the number of atomic-resolution structures of GPCRs has increased rapidly, providing insights into drug binding at the molecular level. These breakthroughs have created excitement regarding the potential of using structural information in ligand design and initiated a new era of rational drug discovery for GPCRs. The molecular docking method is now widely applied to model the three-dimensional structures of GPCR-ligand complexes and screen for chemical probes in large compound libraries. In this review article, we first summarize the current structural coverage of the GPCR superfamily and the understanding of receptor-ligand interactions at atomic resolution. We then present the general workflow of structure-based virtual screening and strategies to discover GPCR ligands in chemical libraries. We assess the state of the art of this research field by summarizing prospective applications of virtual screening based on experimental structures. Strategies to identify compounds with specific efficacy and selectivity profiles are discussed, illustrating the opportunities and limitations of the molecular docking method. Our overview shows that structure-based virtual screening can discover novel leads and will be essential in pursuing the next generation of GPCR drugs.},
keywords = {GPCR, Molecular Docking, Review, Structure-Based Drug Design, Virtual Screening},
pubstate = {published},
tppubtype = {article}
}
Kapla, Jon; Espigares, Ismael Rodriguez; Ballante, Flavio; Selent, Jana; Carlsson, Jens
Can molecular dynamics simulations improve the structural accuracy and virtual screening performance of GPCR models? Journal Article
In: PLOS Computational Biology, 2021.
Links | BibTeX | Tags: GPCR, Molecular Docking, Molecular Dynamics, Molecular Modeling
@article{Kapla2021,
title = {Can molecular dynamics simulations improve the structural accuracy and virtual screening performance of GPCR models? },
author = {Jon Kapla and Ismael Rodriguez Espigares and Flavio Ballante and Jana Selent and Jens Carlsson
},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008936},
doi = {10.1371/journal.pcbi.1008936},
year = {2021},
date = {2021-05-13},
journal = {PLOS Computational Biology},
keywords = {GPCR, Molecular Docking, Molecular Dynamics, Molecular Modeling},
pubstate = {published},
tppubtype = {article}
}
2019
Ballante, Flavio; Rudling, Axel; Zeifman, Alexey; Luttens, Andreas; Vo, Duy Duc; Irwin, John; Kihlberg, Jan; Brea, José; Loza, Maria; Carlsson, Jens
Docking finds GPCR ligands in dark chemical matter Journal Article
In: Journal of Medicinal Chemistry, Just accepted manuscript , 2019.
Abstract | Links | BibTeX | Tags: Biochemistry, Dark Chemical Matter, GPCR, Molecular Docking, Virtual Screening
@article{Ballante2019,
title = {Docking finds GPCR ligands in dark chemical matter},
author = {Flavio Ballante and Axel Rudling and Alexey Zeifman and Andreas Luttens and Duy Duc Vo and John Irwin and Jan Kihlberg and José Brea and Maria Loza and Jens Carlsson},
url = {https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01560},
year = {2019},
date = {2019-12-17},
journal = {Journal of Medicinal Chemistry},
volume = {Just accepted manuscript},
abstract = {High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting-points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A2A adenosine and the D4 dopamine receptors were carried out and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered and the most potent had submicromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.},
keywords = {Biochemistry, Dark Chemical Matter, GPCR, Molecular Docking, Virtual Screening},
pubstate = {published},
tppubtype = {article}
}