Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors: What Can Molecular Docking Do for You?
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Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors : What Can Molecular Docking Do for You? / Ballante, Flavio; Kooistra, Albert J.; Kampen, Stefanie; de Graaf, Chris; Carlsson, Jens.
In: Pharmacological Reviews, Vol. 73, No. 4, 2021, p. 527-565.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors
T2 - What Can Molecular Docking Do for You?
AU - Ballante, Flavio
AU - Kooistra, Albert J.
AU - Kampen, Stefanie
AU - de Graaf, Chris
AU - Carlsson, Jens
PY - 2021
Y1 - 2021
N2 - 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 threedimensional 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. Significance Statement--Extraordinary advances in the structural biology of G protein-coupled receptors have revealed the molecular details of ligand recognition by this large family of therapeutic targets, providing novel avenues for rational drug design. Structure-based docking is an efficient computational approach to identify novel chemical probes from large compound libraries, which has the potential to accelerate the development of drug candidates.
AB - 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 threedimensional 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. Significance Statement--Extraordinary advances in the structural biology of G protein-coupled receptors have revealed the molecular details of ligand recognition by this large family of therapeutic targets, providing novel avenues for rational drug design. Structure-based docking is an efficient computational approach to identify novel chemical probes from large compound libraries, which has the potential to accelerate the development of drug candidates.
KW - STRUCTURE-BASED DISCOVERY
KW - ADENOSINE A(2A) RECEPTOR
KW - STRUCTURE-BASED PREDICTION
KW - KAPPA-OPIOID RECEPTOR
KW - FRAGMENT-LIKE LIGANDS
KW - CRYSTAL-STRUCTURE
KW - DRUG DISCOVERY
KW - BETA(2)-ADRENERGIC RECEPTOR
KW - ALLOSTERIC MODULATORS
KW - INTERNATIONAL UNION
U2 - 10.1124/pharmrev.120.000246
DO - 10.1124/pharmrev.120.000246
M3 - Review
C2 - 34907092
VL - 73
SP - 527
EP - 565
JO - Pharmacological Reviews
JF - Pharmacological Reviews
SN - 0031-6997
IS - 4
ER -
ID: 291671652