Structure-based virtual screening discovers potent and selective adenosine A receptor antagonists.

Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A and A adenosine receptors (AR and AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify AR selective ligands.

Design of Drug Efficacy Guided by Free Energy Simulations of the β -Adrenoceptor.

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds.

Structure-Based Discovery of Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5.

Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu) were performed. The mGlu receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu receptor activity can be allosterically modulated by negative or positive allosteric modulators.

Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors: What Can Molecular Docking Do for You?

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.

Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology.

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented.

StructureProfiler: an all-in-one tool for 3D protein structure profiling.

Motivation: Three-dimensional protein structures are important starting points for elucidating protein function and applications like drug design. Computational methods in this area rely on high quality validation datasets which are usually manually assembled. Due to the increase in published structures as well as the increasing demand for specially tailored validation datasets, automatic procedures should be adopted.